Monocyclic heterocycles as kinase inhibitors

ABSTRACT

The present invention is directed to compounds having the formula 
     
       
         
         
             
             
         
       
     
     and methods for using them for the treatment of cancer.

RELATED APPLICATIONS

This application claims priority and is a divisional application of U.S.application Ser. No. 11/111,144, filed Apr. 21, 2005, which claims thebenefit of priority of U.S. Provisional Applications Nos. 60/564,842,filed Apr. 23, 2004, and 60/639,178, filed Dec. 23, 2004, which parentand provisional applications are incorporated herein by reference intheir entirety.

FIELD OF THE INVENTION

This invention relates to compounds that inhibit the protein tyrosinekinase activity of growth factor receptors such as c-Met, thereby makingthem useful as anti-cancer agents. The pharmaceutical compositions thatcomprise these compounds are also useful in the treatment of diseases,other than cancer, which are associated with signal transductionpathways operating through growth factor and anti-angiogenesis receptorssuch as c-Met.

BACKGROUND

Hepatocyte growth factor (HGF), also known as scatter factor (SF),because of its ability to disrupt colony formation in vitro, is amesenchymally derived cytokine known to induce multiple pleiotropicresponses in normal and neoplastic cells (Sonnenberg et al., J. CellBiol. 123:223-235, 1993; Matsumato et al., Crit. Rev. Oncog. 3:27-54,1992; and Stoker et al., Nature 327:239-242, 1987). These responses areknown to include proliferation in both epithelial and endothelial cells,dissociation of epithelial colonies into individual cells, stimulationof motility (motogenesis) of epithelial cells, cell survival, inductionof cellular morphogenesis (Montesano et al., Cell 67:901-908, 1991), andpromotion of invasion (Stella et al., Int. J. Biochem. Cell Biol.12:1357-62, 1999 and Stuart et al., Int. J. Exp. Path. 81:17-30, 2000),all critical processes underlying metastasis. HGF has also been reportedto promote angiogenesis (Bussolino et al., J. Cell Biol. 119:629-641,1992). In addition, HGF plays a critical role in tissue regeneration,wound healing, and normal embryonic processes, all of which aredependent on both cell motility and proliferation.

HGF initiates these physiological processes through high affinitybinding to its cognate receptor, the Met protein tyrosine kinasereceptor, an identified protooncogene (Park et al., Proc. Natl. Acad.Sci. USA 84:6379-83, 1987 and Bottaro et al., Science 251:802-4, 1991).The mature form of Met consists of a highly glycosylated externalα-subunit as well as a β-subunit with a large extracellular domain, atransmembrane segment and a cytoplasmic tyrosine kinase domain. Ligandengagement induces Met dimerization that results in anautophosphorylated activated receptor. Activation of Met promotes signaltransduction cascades as defined by transphosphorylation of keycytoplasmic tyrosine residues responsible for recruiting multipleeffector proteins (Furge et al., Oncogene 19:5582-9, 2000). Theseinclude the p85 subunit of the PI3-kinase, phospholipase Cγ (Gaul etal., Oncogene 19:1509-18, 2000), Grb2 and Shc adaptor proteins, theprotein phosphatase SHP2 and Gab1. The latter adapter has emerged as themajor downstream docking molecule that becomes tyrosine phosphorylatedin response to ligand occupancy (Schaeper et al., J. Cell Biol.149:1419-32, 2000; Bardelli, et al., Oncogene 18:1139-46, 1999 and Sachset al., J. Cell Biol. 150:1375-84, 2000). Activation of other signalingmolecules has been reported in HGF stimulated cells, most notably Ras,MAP kinases, STATs, ERK-1, -2 and FAK (Tanimura et al., Oncogene17:57-65, 1998; Lai et al., J. Biol. Chem. 275:7474-80 2000 and Furge etal., Oncogene 19:5582-9, 2000). The role of many of these signalingmolecules has been well established in cell proliferation.

Met, also referred to as hepatocyte growth factor receptor (HGFR), isexpressed predominantly in epithelial cells but has also been identifiedin endothelial cells, myoblasts, hematopoietic cells and motor neurons.Overexpression of HGF and activation of Met has been associated with theonset and progression in a number of different tumor types as well as inthe promotion of metastatic disease. Initial evidence linking Met tocancer has been supported by the identification of kinase domainmissense mutations, which predisposes individuals to papillary renalcarcinomas (PRC) and hepatocellular carcinomas (HCC) (Lubensky et al.,Amer. J. Pathology, 155:517-26, 1999). Mutated forms of Met have alsobeen identified in ovarian cancer, childhood HCC, gastric carcinoma,head and neck squamous cell carcinoma, non-small cell lung carcinoma,colorectal metastasis (Christensen et al., Cancer Res., 63:7345-55,2003; Lee et al., Oncogene, 19:4947-53, 2000 and Direnzo et al., Clin.Cancer Res., 1:147-54, 1995). In addition, further evidence supportingthe role of the Met in cancer is based on the overexpression of HGF andMet receptor in various tumors including thyroid, ovarian and pancreaticcarcinomas. It has also been demonstrated to be amplified in livermetastases of colorectal carcinomas (Rong et al. Cancer Res.55:1963-1970, 1995; Rong et al., Cancer Res. 53:5355-5360, 1993;Kenworthy et al., Br. J. Cancer 66:243-247, 1992 and Scarpino et al. J.Pathology 189:570-575, 1999). TPR-Met (an activated form similar toBCR/Abl in CML) has been described and identified in human gastriccarcinoma (PNAS 88:4892-6, 1991). In patients with invasive breastcarcinoma and in a recent study in non small cell lung cancer patients,expression of either the receptor or ligand is a predictor of decreasedsurvival, further linking Met to tumor progression (Camp et al., Cancer86:2259-65 1999 and Masuya et al., Br. J. Cancer, 90:1555-62, 2004). Ingeneral, most human tumors and tumor cell lines of mesenchymal origininappropriately express HGFR and/or HGF.

Numerous experimental data support the role of HGF and Met in tumorinvasion, growth, survival and progression ultimately leading tometastases. Preclinically, transgenic expression of HGF results in ametastatic phenotype (Takayama et al., PNAS, 94:701-6, 1997) and anamplified/overexpressed Met spontaneously transforms NIH-3T3 cells(Cooper et al., EMBO J., 5:2623-8, 1986).

Biological agents, such as ribozymes, antibodies and antisense RNAtargeting either HGF or Met have been shown to inhibit tumorogenesis(Stabile et al., Gene Therapy, 11:325-35, 2004, Jiang et al., Clin.Cancer Res, 9:4274-81, 2003 and Genentech U.S. Pat. No. 6,214,344,2001). Thus, selective, small molecule kinase modulators targeting Metare expected to have therapeutic potential for the treatment of cancersin which Met receptor activation plays a critical role in thedevelopment and progression of primary tumors and secondary metastases.

SUMMARY OF THE INVENTION

The present invention is directed to compounds having Formulas I and IIas described below that are useful in the treatment of cancer.

or an enantiomer, diastereomer, hydrate, solvate or pharmaceuticallyacceptable salt thereof wherein:

R¹ is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,arylalkyl, substituted arylalkyl, aryl, substituted aryl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, heteroaryl,substituted heteroaryl, heterocyclo, substituted heterocyclo,heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, orsubstituted heterocycloalkyl;

each R² is independently H, halogen, cyano, NO₂, OR⁵, NR⁶R⁷, alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclo, substitutedheterocyclo, aryalkyl, substituted arylalkyl, heterocycloalkyl, orsubstituted heterocycloalkyl;

B is O, NR⁸, NR⁸CH₂, S, SO, SO₂, or CR⁹R¹⁰;

V is NR¹¹ or —(CR³⁷R³⁸)_(p)— provided that when VR¹¹ is N, R¹ is analkyl or cycloalkyl;

W and X are each independently C or N;

Y is selected from O, S, and NR¹²;

Z is —CR¹³R¹⁴—, or —(CR¹³R¹⁴)_(l)NR¹⁵;

l is 0 to 2;

n is 0 to 4 if W and X are both C, 0 to 3 if one of X or W is N, and 0to 2 if X and W are both N;

p is 1 to 4;

R³, R⁵, R⁶, R⁷, R⁸, R¹¹ and R¹⁵ are independently selected from H,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclo,substituted heterocyclo;

R⁴ is selected from aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocycloalkyl, and substituted heterocycloalkyl, providedthat

(a) if R⁴ is phenyl

-   -   (i) R⁴ is not substituted with both hydroxy and amido; and    -   (ii) R⁴ is not substituted with —NRSO₂R— wherein R is alkyl or        aryl;

(b) if R⁴ is pyridyl, R⁴ is not substituted with both hydroxy andmethoxy; and

(c) if R⁴ is pyrimidinyl, it is not substituted with ═O;

R⁹ and R¹⁰ are independently selected from H, halogen, alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, orsubstituted heterocycloalkyl;

R¹² is selected from H, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, CN, NO₂ or SO₂NH₂;

R¹³ and R¹⁴ are independently selected from H, halogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocycloalkyl, substitutedheterocycloalkyl or taken together to form a carbocyclic or heterocyclicring of 3 to 8 atoms;

A is selected from one of the following:

wherein

D is S or O;

m is 0 to 6;

R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶ and R²⁷ areindependently selected from H, halogen, NR³⁰R³¹, OR³², CO₂R³³,CONR³⁴R³⁵, SO₂R³⁶, alkyl, substituted alkyl, cycloalkyl, substitutedcycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,—CN, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocycloalkyl, or substituted heterocycloalkyl;

R²⁸ and R²⁹ are independently selected from H, alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, or takentogether to form a carbocyclic or heterocyclic ring of 3 to 8 atoms;

R³⁰, R³¹, R³², R³³, R³⁴, R³⁵, and R³⁶ are independently selected from H,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, alkoxycarbonyl,aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclo,substituted heterocyclo, heterocycloalkyl, or substitutedheterocycloalkyl; and

R³⁷ and R³⁸ are each independently H, halogen, or alkyl.

DESCRIPTION OF THE INVENTION

The present invention provides for compounds of Formulas I and IIdefined above, pharmaceutical compositions employing such compounds, andmethods of using such compounds in the treatment of cancer.

The term “alkyl” herein alone or as part of another group refers to amonovalent alkane (hydrocarbon) derived radical containing from 1 to 12carbon atoms unless otherwise defined. Preferred alkyl groups are loweralkyl groups having from 1 to 6 carbon atoms. An alkyl group is anoptionally substituted straight, branched or cyclic saturatedhydrocarbon group. Alkyl groups may be substituted at any availablepoint of attachment. An alkyl group substituted with another alkyl groupis also referred to as a “branched alkyl group”. Exemplary alkyl groupsinclude methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl,pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like.Exemplary substituents include but are not limited to one or more of thefollowing groups: alkyl, cycloalkyl, heterocycloalkyl, —CN, aryl,heteroaryl, halo (such as F, Cl, Br, I), haloalkyl (such as CCl₃ orCF₃), hydroxyl, alkoxy, alkylthio, alkylamino, —COOH, —COOR, —C(O)R,—OCOR, amino, carbamoyl (—NHCOOR— or —OCONHR—), urea (—NHCONHR—) orthiol (—SH).

The term “alkenyl” herein alone or as part of another group refers to ahydrocarbon radical straight, branched or cyclic containing from 2 to 12carbon atoms and at least one carbon to carbon double bond. Alkenylgroups may also be substituted at any available point of attachment.Exemplary substituents for alkenyl groups include those listed above foralkyl groups.

The term “alkynyl” herein alone or as part of another group refers to ahydrocarbon radical straight, branched or cyclic containing from 2 to 12carbon atoms and at least one carbon to carbon triple bond. Alkynylgroups may also be substituted at any available point of attachment.Exemplary substituents for alkynyl groups include those listed above foralkyl groups.

The numbers in the subscript after the symbol “C” define the number ofcarbon atoms a particular group can contain. For example “C₁₋₆ alkyl”means a straight or branched saturated carbon chain having from one tosix carbon atoms; examples include methyl, ethyl, n-propyl, isopropyl,n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl, sec-pentyl, isopentyl,and n-hexyl. Depending on the context, “C₁₋₆ alkyl” can also refer toC₁₋₆ alkylene which bridges two groups; examples includepropane-1,3-diyl, butane-1,4-diyl, 2-methyl-butane-1,4-diyl, etc. “C₂₋₆alkenyl” means a straight or branched carbon chain having at least onecarbon-carbon double bond, and having from two to six carbon atoms;examples include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl,pentenyl, and hexenyl. Depending on the context, “C₂₋₆ alkenyl” can alsorefer to C₂₋₆ alkenediyl which bridges two groups; examples includeethylene-1,2-diyl (vinylene), 2-methyl-2-butene-1,4-diyl,2-hexene-1,6-diyl, etc. “C₂₋₆ alkynyl” means a straight or branchedcarbon chain having at least one carbon-carbon triple bond, and from twoto six carbon atoms; examples include ethynyl, propynyl, butynyl, andhexynyl.

The term “cycloalkyl” herein alone or as part of another group is aspecies of alkyl containing from 3 to 15 carbon atoms, withoutalternating or resonating double bonds between carbon atoms. It maycontain from 1 to 4 rings. Exemplary groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, etc. Cycloalkyl groupsmay be substituted at any available point of attachment. Exemplarysubstituents include one or more of the following groups: halogen, suchas F, Br, or Cl, hydroxyl, alkyl, alkoxy, amino, nitro, cyano, thiol,alkylthio, and any of the substituents described above for alkyl groups.

The terms “alkoxy” or “alkylthio” herein alone or as part of anothergroup denote an alkyl group as described above bonded through an oxygenlinkage (—O—) or a sulfur linkage (—S—), respectively.

The term “alkyloxycarbonyl” herein alone or as part of another groupdenotes an alkoxy group bonded through a carbonyl group. Analkoxycarbonyl radical is represented by the formula: —C(O)OR, where theR group is a straight or branched C₁₋₆ alkyl group, cycloalkyl, aryl, orheteroaryl.

The term “alkylcarbonyl” herein alone or as part of another group refersto an alkyl group bonded through a carbonyl group.

The term “alkylcarbonyloxy” herein alone or as part of another groupdenotes an alkylcarbonyl group bonded through an oxygen linkage.

The term “aryl” herein alone or as part of another group refers tomonocyclic or bicyclic aromatic rings, e.g. phenyl, substituted phenyland the like, as well as groups which are fused, e.g., napthyl,phenanthrenyl and the like. An aryl group thus contains at least onering having at least 6 atoms, with up to five such rings being present,containing up to 22 atoms therein, with alternating (resonating) doublebonds between adjacent carbon atoms or suitable heteroatoms. Aryl groupsmay optionally be substituted with one or more groups including, but notlimited to halogen, alkyl, alkoxy, hydroxy, carboxy, carbamoyl,alkyloxycarbonyl, nitro, alkenyloxy, trifluoromethyl, amino, cycloalkyl,aryl, heteroaryl, cyano, alkyl S(O)_(m) (m=0, 1, 2), or thiol.

The term “arylalkyl” or “aralkyl” herein alone or as part of anothergroup denotes an aryl group as described above bonded through an alkylgroup, as described above. And example of an aralkyl group is a benzylgroup.

The term “amino” herein alone or as part of another group refers to—NH₂. An “amino” may optionally be substituted with one or twosubstituents, which may be the same or different, such as alkyl, aryl,arylalkyl, alkenyl, alkynyl, heteroaryl, heteroarylalkyl,cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl,haloalkyl, hydroxyalkyl, alkoxyalkyl, thioalkyl, carbonyl or carboxyl.These substituents may be further substituted with a carboxylic acid,any of the alkyl or aryl substituents set out herein. In someembodiments, the amino groups are substituted with carboxyl or carbonylto form N-acyl or N-carbamoyl derivatives

The term “heteroaryl” herein alone or as part of another group refers tosubstituted and unsubstituted aromatic 5 or 6 membered monocyclicgroups, 9 or 10 membered bicyclic groups, and 11 to 14 memberedtricyclic groups which have at least one heteroatom (O, S or N) in atleast one of the rings. Each ring of the heteroaryl group containing aheteroatom can contain one or two oxygen or sulfur atoms and/or from oneto four nitrogen atoms provided that the total number of heteroatoms ineach ring is four or less and each ring has at least one carbon atom.The fused rings completing the bicyclic and tricyclic groups may containonly carbon atoms and may be saturated, partially saturated, orunsaturated. The nitrogen and sulfur atoms may optionally be oxidizedand the nitrogen atoms may optionally be quaternized. Heteroaryl groupswhich are bicyclic or tricyclic must include at least one fully aromaticring but the other fused ring or rings may be aromatic or non-aromatic.The heteroaryl group may be attached at any available nitrogen or carbonatom of any ring. The heteroaryl ring system may contain zero, one, twoor three substituents selected from the group consisting of halo, alkyl,substituted alkyl, alkenyl, alkynyl, aryl, nitro, cyano, hydroxy,alkoxy, thioalkyl, ═O, —CO₂H, —C(═O)H, —CO₂-alkyl, —C(═O)alkyl, phenyl,benzyl, phenylethyl, phenyloxy, phenylthio, cycloalkyl, substitutedcycloalkyl, heterocyclo, heteroaryl, —NR′R″, —C(═O)NR′R″, —CO₂NR′R″,—C(═O)NR′R″, —NR′CO₂R″, —NR′C(═O)R″, —SO₂NR′R″, and —NR′SO₂R″, whereineach of R′ and R″ is independently selected from hydrogen, alkyl,substituted alkyl, and cycloalkyl, or R′ and R″ together form aheterocyclo or heteroaryl ring.

Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl,pyrazolinyl, imidazolyl, oxazolyl, diazolyl, isoxazolyl, thiazolyl,thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like.

Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl,benzodioxolyl, benzoxaxolyl, benzothienyl, quinolinyl,tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl,indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl,cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl,dihydroisoindolyl, tetrahydroquinolinyl and the like.

Exemplary tricyclic heteroaryl groups include carbazolyl, benzidolyl,phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl and the like.

The term “heterocyclic ring” herein alone or as part of another grouprefers to a stable, saturated, or partially unsaturated monocyclic ringsystem containing 5 to 7 ring members of carbon atoms and other atomsselected from nitrogen, sulfur and/or oxygen. Preferably, a heterocyclicring is a 5 or 6-membered monocyclic ring and contains one, two, orthree heteroatoms selected from nitrogen, oxygen and/or sulfur. Theheterocyclic ring may be optionally substituted which means that theheterocyclic ring may be substituted at one or more substitutable ringpositions by one or more groups independently selected from alkyl(preferably lower alkyl), alkoxy (preferably lower alkoxy), nitro,monoalkylamino (preferably a lower alkylamino), dialkylamino (preferablya di[lower]alkylamino), cyano, halo, haloalkyl (preferablytrifluoromethyl), alkanoyl, aminocarbonyl, monoalkylaminocarbonyl,dialkylaminocarbonyl, alkyl amido (preferably lower alkyl amido),alkoxyalkyl (preferably a lower alkoxy[lower]alkyl), alkoxycarbonyl(preferably a lower alkoxycarbonyl), alkylcarbonyloxy (preferably alower alkylcarbonyloxy) and aryl (preferably phenyl), said aryl beingoptionally substituted by halo, lower alkyl and lower alkoxy groups.Examples of such heterocyclic rings are isoxazolyl, imidazolinyl,thiazolinyl, imidazolidinyl, pyrrolyl, pyrrolinyl, pyranyl, pyrazinyl,piperidyl, morpholinyl and triazolyl. The heterocyclic ring may beattached to the parent structure through a carbon atom or through anyheteroatom of the heterocyclyl that results in a stable structure.

The term “heteroatom” means O, S or N, selected on an independent basis.It should be noted that any heteroatom with unsatisfied valences isassumed to have the hydrogen atom to satisfy the valences.

The term “halogen” or “halo” refers to chlorine, bromine, fluorine oriodine selected on an independent basis.

When a functional group is termed “protected”, this means that the groupis in modified form to preclude undesired side reactions at theprotected site. Suitable protecting groups for the compounds of thepresent invention will be recognized from the present application takinginto account the level of skill in the art, and with reference tostandard textbooks, such as Greene, T. W. et al., Protective Groups inOrganic Synthesis, Wiley, N.Y. (1991).

As used herein, the term “patient” encompasses all mammalian species.

Suitable examples of salts of the compounds according to the inventionwith inorganic or organic acids are hydrochloride, hydrobromide,sulfate, methanesulfonate, maleate, fumarate, and phosphate. Salts whichare unsuitable for pharmaceutical uses but which can be employed, forexample, for the isolation or purification of free compounds I or II,their pharmaceutically acceptable salts, are also included.

In general, the instant invention comprises compounds having Formula Ior II:

or an enantiomer, diastereomer, hydrate, solvate or pharmaceuticallyacceptable salt thereof wherein:

R¹ is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,arylalkyl, substituted arylalkyl, aryl, substituted aryl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, heteroaryl,substituted heteroaryl, heterocyclo, substituted heterocyclo,heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, orsubstituted heterocycloalkyl;

each R² is independently H, halogen, cyano, NO₂, OR⁵, NR⁶R⁷, alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclo, substitutedheterocyclo, aryalkyl, substituted arylalkyl, heterocycloalkyl, orsubstituted heterocycloalkyl;

B is O, NR⁸, NR⁸CH₂, S, SO, SO₂, or CR⁹R¹⁰;

V is NR¹¹ or —(CR³⁷R³⁸)_(p)— provided that when V is N, R¹ is an alkylor cycloalkyl;

W and X are each independently C or N;

Y is selected from O, S, and NR¹²;

Z is —CR¹³R¹⁴—, or —(CR¹³R¹⁴)_(l)NR¹⁵;

l is 0 to 2;

n is 0 to 4 if W and X are both C, 0 to 3 if one of X or W is N, and 0to 2 if X and W are both N;

p is 1 to 4;

R³, R⁵, R⁶, R⁷, R⁸, R¹¹ and R¹⁵ are independently selected from H,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclo,substituted heterocyclo;

R⁴ is selected from aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocycloalkyl, and substituted heterocycloalkyl, providedthat

(a) if R⁴ is phenyl

-   -   (i) R⁴ is not substituted with both hydroxy and amido; and    -   (ii) R⁴ is not substituted with —NRSO₂R— wherein R is alkyl or        aryl;

(b) if R⁴ is pyridyl, R⁴ is not substituted with both hydroxy andmethoxy; and

(c) if R⁴ is pyrimidinyl, it is not substituted with ═O;

R⁹ and R¹⁰ are independently selected from H, halogen, alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, orsubstituted heterocycloalkyl;

R¹² is selected from H, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, CN, NO₂ or SO₂NH₂;

R¹³ and R¹⁴ are independently selected from H, halogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocycloalkyl, substitutedheterocycloalkyl or taken together to form a carbocyclic or heterocyclicring of 3 to 8 atoms;

A is selected from one of the following:

wherein

D is S or O;

m is 0 to 6;

R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶ and R²⁷ areindependently selected from H, halogen, NR³⁰R³¹, OR³², CO₂R³³,CONR³⁴R³⁵, SO₂R³⁶, alkyl, substituted alkyl, cycloalkyl, substitutedcycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,—CN, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocycloalkyl, or substituted heterocycloalkyl;

R²⁸ and R²⁹ are independently selected from H, alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, or takentogether to form a carbocyclic or heterocyclic ring of 3 to 8 atoms;

R³⁰, R³¹, R³², R³³, R³⁴, R³⁵, and R³⁶ are independently selected from H,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, alkoxycarbonyl,aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclo,substituted heterocyclo, heterocycloalkyl, or substitutedheterocycloalkyl; and

R³⁷ and R³⁸ are each independently H, halogen, or alkyl.

In some embodiments of the present invention, R¹ is a substituted orunsubstituted phenyl, such as fluorophenyl, a substituted orunsubstituted C₁ to C₄ alkyl, such as methyl, or a substituted orunsubstituted C₃ to C₈ cycloalkyl, such as cyclohexyl or cyclopentyl.

In some embodiments of the present invention, R² is C₁ to C₄ alkyl,halogen, or haloalkyl.

In some embodiments of the present invention, R⁴ is optionallysubstituted phenyl, or a 5 or 6 membered nitrogen containing heteroarylgroup such as pyridyl, pyridinone, pyrazolyl, or pyrrolidyl.

According to one embodiment of the present invention, B is O, NHCH₂, CH₂or CH(OH); Y is O or S and Z is —CR¹³R¹⁴ or —NR¹⁵ wherein R¹³, R¹⁴, andR¹⁵ are each H.

In some embodiments of the present invention, A is an optionallysubstituted pyridine or pyrimidine, wherein the substituent is alkyl,alkenyl, alkynyl, halogen, cycloalkyl, heterocycloalkyl, —NR³⁹COR⁴⁰,—NR³⁹C(O)₂R⁴⁰, —NR⁴¹R⁴², or —C(O)NR⁴³R⁴⁴, wherein R³⁹, R⁴⁰, R⁴¹, R⁴²,R⁴³, and R⁴⁴ are independently H, lower alkyl, substituted lower alkyl,hydroxyalkyl, aminoalkyl, cycloalkyl, substituted cycloalkyl,heterocycloalkyl, substituted heterocycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, or —NR⁴³R⁴⁴ form a heterocycloalkyl.

According to some embodiments of the present invention, A is a pyridinesubstituted with —NR⁴¹R⁴², —NR³⁹COR⁴⁰, —C(O)NR⁴³R⁴⁴, halogen, C₁ to C₄alkyl, optionally substituted with hydroxy, hydroxyalkylamino,alkylamino, aminoalkylamino, or heteroarylalkyl; or —C═C—R⁴⁵, —C≡R⁴⁶,wherein R⁴⁵ and R⁴⁶ are alkyl, hydroxyalkyl, aminoalkyl, cycloalkyl,heterocycloalkyl, —C(O)R⁴⁷, —NR³⁹COR⁴⁰, aryl, or heteroaryl; or thepyridine is substituted with aryl, such as phenyl, which may be furthersubstituted with CONH₂, methyl, aminoethyl, hydroxyethyl,—CONHCH₂CH₂NHCH₃, or CH₂CONH₂; the pyridines may also be substitutedwith pyridyl or piperidyl groups.

According to some embodiments of the present invention, A is anoptionally substituted pyrimidine. Preferred substituents include—NR⁴¹R⁴², or —NR³⁹CO₂R⁴⁰, wherein R⁴¹ and R⁴² are preferably H or methyland R³⁹ and R⁴⁰ are preferably, H or alkyl.

In one embodiment of the present invention, compounds have the followingformula III:

wherein

R¹ is optionally substituted phenyl or alkyl; Z is NH or NCH₃; R² is F,Cl, CH₃ or CF₃; R³ is H; and Y is O or S. In some embodiments, R¹ is C₃to C₇ cycloalkyl, substituted or unsubstituted phenyl, or —(CH₂)—R⁵⁰wherein n is 1 to 3, R⁵⁰ is H, substituted or unsubstituted phenyl,amino, amido, CN, —C(O)₂H, or —C(O)₂CH₃.

In some embodiments of the present invention, compounds have thefollowing formula Formula IV:

wherein R² is halo or H; R³ is H; R⁴ is optionally substituted phenyl,optionally substituted pyrazole, or optionally substituted pyridyl,pyridinone, or pyridine-N-oxide.

In one embodiment of the present invention, compounds are of thefollowing formula V:

wherein R¹ is optionally alkyl or cycloalkyl; A is optionallysubstituted pyrimidine or pyridine; and R₂ is halo or H; and R¹³ and R¹⁴are either H or together with the carbon to which they are attached forma cycloalkyl, such as cyclopropyl.

The invention also provides methods for treating a proliferativedisease, such as cancer by administering to a mammalian species in needof such treatment an effective amount of a compound of formulas I or II,as defined above. In another embodiment, the invention provides a methodfor treating a proliferative disease via modulation of Met kinase byadministering to a mammalian species in need of such treatment aneffective amount of a compound of formulas I or II, as defined above, incombination (simultaneously or sequentially) with at least one otheranti-cancer agent. In a preferred embodiment, the proliferative diseaseis cancer.

Certain compounds of Formulas I and II may generally be preparedaccording to the following Schemes 1-14. The compounds are synthesizedreadily using synthetic methods known to one skilled in the art.Solvates (e.g., hydrates) of the compounds of Formulas I and II are alsowithin the scope of the present invention. Methods of solvation aregenerally known in the art. Accordingly, the compounds of the instantinvention may be in the free or hydrate form, and may be obtained bymethods exemplified by the following schemes below.

General routes to the pyridine and pyrimidine analogues described in theinvention are illustrated in Scheme 1. An appropriately substitutedpyridine or pyrimidine 1 can be treated with functionalized phenols 2,4, and 8 in the presence of a base, such as sodium hydride, sodiumhydroxide, or potassium carbonate, to furnish the desired ethers 3, 5,and 9, respectively. Removal of the acetamide protecting group ofcompound 3 with aqueous HCl in methanol provides the key intermediate 5.Alternatively, aniline 5 can be obtained from compound 9 via reductionof the nitro group with either zinc dust and ammonium chloride or Adams'catalyst (platinum (IV) oxide) under hydrogenation conditions. Analogues6 and 7 can then be prepared by acylation of aniline 5 with, for exampleisocyanates, acid chlorides or by treatment with a carboxylic acid and acoupling reagent, such as:benzotriazol-1-yloxytris(trimethylamino)phosphonium hexafluorophosphate(BOP reagent), bromotripyrrolidinophosphonium hexafluorophosphate(PyBroP), O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TBTU). Formation of the acylthiourea of 6 (Y=S, Z=NH)can be accomplished by treating aniline 5 with an appropriatelysubstituted isothiocyanate.

The two different regioisomeric aminopyrimidine analogues 14 and 19 canbe prepared using the synthetic routes outlined in Schemes 2 and 3.PMB-protected aminopyrimidine 11, derived from commercially available2,4-dichloropyrimidine (10, Aldrich), can be converted to ether 13 viaaniline 12 using the same chemistry outlined in Scheme 1. Removal of thePMB group of 13 can be accomplished with trifluoroacetic acid andanisole to generate compound 14.

Similarly, PMB-protected aminopyrimidine 16, derived from commerciallyavailable 4,6-dichloropyrimidine (15, TCI America), can be converted toether 17 following the PMB deprotection step (Scheme 3). Bis-Boc(t-butyloxycarbonyl) protection of the amine of 17 with excessdi-tert-butyl dicarbonate followed by hydrogenation with Adams' catalystprovides aniline 18. Amine 19 can be obtained from compound 18 followingan acylation or thiourea formation step and removal of the Bocprotecting groups under acidic conditions.

Aminopyridazine derivative 26 may be prepared using the synthetic routeoutlined in Scheme 4 which is based on similar chemistry cited in thefollowing references: Chung, H.-A. et al. J. Heterocyclic Chem. 1999,36, 905-910 and Bryant R. D. et al. J. Heterocyclic Chem. 1995, 32,1473-1476, the disclosures of which are herein incorporated byreference. 4,5-Dichloropyridazin-3(2H)-one (20, Aldrich) can beprotected with, for example a tetrahydropyran (THP) group to giveintermediate 21. Treatment of compound 21 with an appropriatelysubstituted phenol and a base (i.e., sodium hydride) followed byreduction of the nitro containing intermediate under catalytichydrogenation conditions can provide aniline 22. Protection of theaniline group of 22 as a bis-benzyl carbamate (Cbz) followed by removalof the THP group under acidic conditions may furnish compound 23.Treatment of compound 23 with either trifluoroacetic anhydride (TFAA),phosphorous oxychloride or phosphorous oxybromide in the presence of abase, such as triethylamine or diisopropylethylamine may introduce thenecessary leaving group at the 3-position of compound 24. Displacementof the leaving group X of compound 24 with an appropriately substitutedamine, followed by removal of the Cbz groups can generate intermediate25. Aniline 25 may be converted to the desired 3-aminopyridazineanalogue 26 using chemistry previously described in Schemes 1-3.

2-Aminopyridine derivatives may be prepared using the synthetic routesoutlined in Schemes 5 and 6. Aniline 27, derived from chemistrydescribed in Scheme 1 may be converted to intermediate 28 upon heatingwith Cu powder and potassium carbonate in benzylamine (Scheme 5).Removal of the benzyl protecting group of compound 28 under catalytichydrogenation conditions with palladium on carbon provides aminopyridine29. Intermediates 28 or 29 can be treated with isothiocyanates 30,isocyanates 32, and carboxylic acids 34 in the presence of a couplingreagent to afford acylthiourea 31, acylurea 33, and amide 35,respectively.

In a related approach, 2-chloropyridine intermediate 36, obtained usingchemistry described in Scheme 1 can be converted to the N-oxide 37 using3-chloroperoxybenzoic acid (m-CPBA) in chloroform (see, WO2004/002410)(Scheme 6). Treatment of compound 37 with an appropriately substitutedamine can afford intermediate 38. Reduction of the N-oxide of compound38 with, for example triphenylphosphine, followed by removal of theacetamide protecting group under acidic conditions can provide aniline39. Conversion of aniline 39 to the desired analogue 40 can beaccomplished using chemistry previously described in Schemes 1-5.

In an alternative approach to compounds related to 40, the2-aminopyridine derivatives 47 and 48 may be prepared according to thesynthetic sequence illustrated in Scheme 7. To this end,4-chloropicolinic acid (41, TCI America) can be converted to4-chloropicolinamide (42) using a two step procedure involvingthionylchloride followed by ammonia in methanol. Coupling ofintermediate 42 with 4-aminophenol derivative 43, in the presence of abase, such as potassium t-butoxide can afford the picolinamidederivative 44. Acylation or acylurea formation of intermediate 44 canprovide intermediates such as 45 and 46. Treatment of the picolinamidederivatives 45 and 46 with either bis-(trifluoroacetoxy)-iodobenzene,pyridine and water in DMF or bromine, potassium hydroxide in waterpromotes a Hofmann rearrangement to generate the desired 2-aminopyridinederivatives 47 and 48.

Thiazole containing compounds 53, 57 and 62 can be prepared using thesynthetic routes described in Schemes 8-10. Displacement of the leavinggroups of 49 (Scheme 8) or 54 (Scheme 9) with an aniline/phenol 50 canprovide intermediates 51 and 55, respectively. Reduction of the nitrosubstituents of 51 and 55 with zinc dust and ammonium chloride in aTHF-MeOH mixture should generate anilines 52 and 56, respectively.Conversion of anilines 52 and 56 to the desired compounds 53 and 57 canbe accomplished using chemistry previously described (vide supra).

Reductive amination of aldehyde 58 can be achieved using the methodsdescribed in WO 2004/001059, herein incorporated by reference in itsentirety, using an appropriately substituted aniline 59 can furnish thenitro intermediate 60 (Scheme 10). The desired aminothiazole derivative62 can then be obtained using chemistry similar to that which wasdescribed in Schemes 8 and 9.

Incorporation of various substituents at the 3-position of the pyridinenucleus can be accomplished using the chemistry outlined in Scheme 11.To this end, 4-chloro-3-iodopyridine (63, Tabanella, S. et al. Org.Biomol. Chem. 2003, 1, 4254-4261.) can be coupled with the 4-nitrophenolderivative 8 in the presence of a base, such as diisopropylethylamine(Hunig's base) to afford the desired iodide intermediate 64. A varietyof organometallic mediated coupling reactions can then be carried outwith the iodide derivative 64, examples of which are illustrated inScheme 11. The iodide 64 can be treated with amines (R″R′NH),substituted alkynes 66, arylboronates 67, vinylstannanes, andα,β-unsaturated esters in the presence of a palladium or copper catalystto afford the intermediates 65, 68-71, respectively. The nitro moiety ofcompounds 65 and 68-71 can be reduced with, for example zinc dust andammonium chloride in a THF-MeOH mixture, and the resulting anilineintermediates can be acylated using chemistry previously described inSchemes 1-5. Intermediate 71 can then be converted to theα,β-unsaturated amides 73 (Scheme 12). Compound 72, derived from acidpromoted hydrolysis of ester 71, can be coupled with various amines(R″R′NH) in the presence of a coupling reagent such as, but not limitedto EDCI, TBTU, DCC, to furnish the desired amide intermediate 73.Reduction of the nitro moiety of 73 and subsequent acylation of therequisite aniline intermediate can be accomplished using chemistrypreviously described in Schemes 1-5.

Intermediate 74 can also be further modified to prepare propargylicamines 76 (Scheme 13). Mesylation of the propargylic alcohol 74, can beaccomplished with methanesulfonyl chloride in the presence of a base,such as diisopropylethylamine (Hunig's base) to provide the mesylate 75.Displacement of the mesylate group of compound 75 with various amines(R″R′NH) can provide the propargylic amines 76. Reduction of the nitromoiety of 76 and subsequent acylation of the requisite anilineintermediate can be accomplished using chemistry previously described inSchemes 1-5.

The 3-aminopyridine derivatives 79 and 80 can be prepared according tothe synthetic route described in Scheme 14. To this end,4-chloro-3-nitropyridine (77, Lancaster Synthesis Ltd.) can be coupledwith 4-aminophenol in the presence of a base, such as sodium hydride inDMF to afford the nitro intermediate 78. Chemistry previously describedabove can be used to convert intermediate 78 to the desired compounds 79and 80. The amino substituent of 79 and 80 can also be further modified,for example via alkylation, acylation, arylation or sulfonylation.

Incorporation of substituents on either the 5- or 3-position of the2-aminopyridine ring can be accomplished using the iodide intermediates83 and 86, respectively (Schemes 15 and 16). The 2-carboxamidederivative 81 can be converted to the 2-aminopyridine derivative 82using the Hofmann rearrangement protocol previously described in Scheme7. Iodination of the 5-position of compound 82 can be achieved withN-iodosuccinimide in an acetonitrile-isopropanol mixture to afford thedesired iodide intermediate 83. Alternatively, t-butyl4-chloropyridin-2-ylcarbamate (84, CB Research and Development Inc.) canbe converted to t-butyl 4-chloro-3-iodopyridin-2-ylcarbamate (85) via atwo step process involving n-butyllithium in THF at low temperaturefollowed by the addition of iodine. Removal of the N-Boc(t-butylcarbamate) protecting group of 85 with refluxing aqueoushydrogen bromide followed by coupling of the chloride intermediate withthe 4-nitrophenol derivative 8 in the presence diisopropylamine (Hunig'sbase) in N-methylpyrrolidinone (NMP) at elevated temperature can providethe iodide intermediate 86. The iodide intermediates 83 and 86 can befurther processed using chemistry similar to that previously describedin Scheme 11.

The methylene linked (B=CH₂) analogues 93 and 94 can be preparedaccording to the synthetic sequence outlined in Scheme 17. Compound 88,derived from N-Boc protection of the 4-bromoaniline derivative 87, canbe treated with methylmagnesium bromide followed by tert-butyllithiumand 2-chloroisonicotinaldehyde (Frey, L. F. et al. Tetrahedron Lett.2001, 42, 6815-6818) at low temperature to provide intermediate 90.Oxidation of the pyridine ring of 90 with 3-chloroperoxybenzoic acid(m-CPBA), followed by displacement of the chloro substituent with anamine (R′NH₂) and subsequent reduction of the N-oxide intermediate withzinc and ammonium formate in methanol can provide intermediate 91. Whenallylamine is used as the nucleophilic amine (R′NH₂), the allyl groupcan be removed from the amine of 91 using a rhodium catalyst in anethanol-water mixture. Removal of the hydroxyl group of 91 can beaccomplished by two different methods. For example, hydrogenolysis ofcompound 91 in the presence of a palladium catalyst, followed bydeprotection of the N-Boc group on the aniline under acidic conditions(HCl in methanol) can afford compound 92. Alternatively, compound 92 canbe obtained by acylation of the alcohol of 91 and subsequenthydrogenolysis of the intermediate in the presence of a palladiumcatalyst and removal of the N-Boc protecting group under acidicconditions (trifluoroacetic acid in methylene chloride). Intermediate 92can then be acylated to furnish the desired compounds 93 and 94 usingchemistry previously described in Schemes 1-5.

The heterocyclic amide derivatives 100 and 105 can be prepared accordingto the synthetic routes described in Schemes 18 and 19. To this end,methyl 2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylate (97) can beobtained in a two step process beginning with commercially available(E)-dimethyl 2-(3-methoxyallylidene)malonate (95) (Scheme 18). Thus,treatment of compound 95 with aniline at room temperature can provideintermediate 96, which can then cyclized in the presence of a base, suchas sodium hydride in dimethylsulfoxide to generate 97. Hydrolysis ofintermediate 97 under basic conditions can provide2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid (98). Thecarboxylic acid 98 can then be coupled with the aniline derivative 99 inthe presence of a coupling reagent, such as1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) andhydroxybenzotriazole (HOBt) in DMF to furnish the desired compound 100.

The pyridyl N-oxide intermediate 104 (Scheme 19) can be obtained by atwo step process in which the commercially available 6-bromopicolinicacid (101) is coupled with the phenyl-1,3,2-dioxaborinane 102 (Aldrich)in the presence of a palladium(0) catalyst and sodium carbonate,followed by oxidation of the requisite intermediate 103 at elevatedtemperature. Coupling of intermediate 104 with the aniline derivative 99can furnish the desired compound 105.

The compounds of Formulas I and II are useful in the treatment of avariety of cancers, including, but not limited to, the following:

(a) carcinoma, including that of the bladder, breast, colon, kidney,liver, lung, including small cell lung cancer, esophagus, gall bladder,ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, includingsquamous cell carcinoma;

(b) hematopoietic tumors of lymphoid lineage, including leukemia, acutelymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma,T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkins lymphoma, hairy celllymphoma and Burkett's lymphoma;

(c) hematopoietic tumors of myeloid lineage, including acute and chronicmyelogenous leukemias, myelodysplastic syndrome and promyelocyticleukemia;

(d) tumors of mesenchymal origin, including fibrosarcoma andrhabdomyosarcoma;

(e) tumors of the central and peripheral nervous system, includingastrocytoma, neuroblastoma, glioma and schwannomas; and

(f) other tumors, including melanoma, seminoma, teratocarcinoma,osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroidfollicular cancer and Kaposi's sarcoma.

Due to the key role protein kinases in the regulation of cellularproliferation in general, inhibitors could act as reversible cytostaticagents which may be useful in the treatment of any disease process whichfeatures abnormal cellular proliferation, e.g., benign prostatichyperplasia, familial adenomatosis polyposis, neuro-fibromatosis,atherosclerosis, pulmonary fibrosis, arthritis, psoriasis,glomerulo-nephritis, restenosis following angioplasty or vascularsurgery, hypertrophic scar formation, inflammatory bowel disease,transplantation rejection, endotoxic shock, and fungal infections.

Compounds of Formulas I and II as modulators of apoptosis, will beuseful in the treatment of cancer (including but not limited to thosetypes mentioned herein above), viral infections (including but notlimited to herpevirus, poxvirus, Epstein-Barr virus, Sindbis virus andadenovirus), prevention of AIDS development in HIV-infected individuals,autoimmune diseases (including but not limited to systemic lupus,erythematosus, autoimmune mediated glomerulonephritis, rheumatoidarthritis, psoriasis, inflammatory bowel disease, and autoimmunediabetes mellitus), neurodegenerative disorders (including but notlimited to Alzheimer's disease, AIDS-related dementia, Parkinson'sdisease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinalmuscular atrophy and cerebellar degeneration), myelodysplasticsyndromes, aplastic anemia, ischemic injury associated with myocardialinfarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis,toxin-induced or alcohol related liver diseases, hematological diseases(including but not limited to chronic anemia and aplastic anemia),degenerative diseases of the musculoskeletal system (including but notlimited to osteoporosis and arthritis) aspirin-sensitive rhinosinusitis,cystic fibrosis, multiple sclerosis, kidney diseases and cancer pain.

Compounds of Formulas I and II may modulate the level of cellular RNAand DNA synthesis. These agents would therefore be useful in thetreatment of viral infections (including but not limited to HIV, humanpapilloma virus, herpesvirus, poxvirus, Epstein-Barr virus, Sindbisvirus and adenovirus).

Compounds of Formulas I and II may be useful in the chemoprevention ofcancer. Chemoprevention is defined as inhibiting the development ofinvasive cancer by either blocking the initiating mutagenic event or byblocking the progression of pre-malignant cells that have alreadysuffered an insult or inhibiting tumor relapse.

Compounds of Formulas I and II may also be useful in inhibiting tumorangiogenesis and metastasis.

The term “anticancer” agent includes any known agent that is useful forthe treatment of cancer including 17α-Ethinylestradiol,Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone,Dromostanolone propionate, Testolactone, Megestrolacetate,Methylprednisolone, Methyl-testosterone, Prednisolone, Triamcinolone,chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine,Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, Zoladex,matrix metalloproteinase inhibitors, VEGF inhibitors, including asanti-VEGF antibodies such as Avastin, and small molecules such as ZD6474and SU6668, vatalanib, BAY-43-9006, SU11248, CP-547632, and CEP-7055 arealso included. Anti-Her2 antibodies from Genentech (such as Herceptin)may also be utilized. Suitable EGFR inhibitors include gefitinib,erlotinib, and cetuximab. Pan Her inhibitors include canertinib,EKB-569, and GW-572016. Also included are Src inhibitors as well asCasodex® (bicalutamide, Astra Zeneca), Tamoxifen, MEK-1 kinaseinhibitors, MAPK kinase inhibitors, PI3 inhibitors, and PDGF inhibitors,such as imatinib. Also included are anti-angiogenic and antivascularagents which, by interrupting blood flow to solid tumors, render cancercells quiescent by depriving them of nutrition. Castration, which alsorenders androgen dependent carcinomas non-proliferative, may also beutilized. Also included are IGF1R inhibitors, inhibitors of non-receptorand receptor tyrosine kinases, and inhibitors of integrin signaling.Additional anticancer agents include microtubule-stabilizing agents suchas paclitaxel (also known as Taxol®), docetaxel (also known asTaxotere®), 7-O-methylthiomethylpaclitaxel (disclosed in U.S. Pat. No.5,646,176), 4-desacetyl-4-methylcarbonatepaclitaxel,3′-tert-butyl-3′-N-tert-butyloxycarbonyl-4-deacetyl-3′-dephenyl-3′-N-debenzoyl-4-O-methoxycarbonyl-paclitaxel(disclosed in U.S. Ser. No. 09/712,352 filed on Nov. 14, 2000), C-4methyl carbonate paclitaxel, epothilone A, epothilone B, epothilone C,epothilone D, desoxyepothilone A, desoxyepothilone B,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7-11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17oxabicyclo[14.1.0]heptadecane-5,9-dione (disclosed in WO 99/02514),[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(aminomethyl)-4-thiazolyl]-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4-17-dioxabicyclo[14.1.0]-heptadecane-5,9-dione(disclosed in U.S. Pat. No. 6,262,094) and derivatives thereof, andmicrotubule-disruptor agents. Also suitable are CDK inhibitors, anantiproliferative cell cycle inhibitor, epidophyllotoxin; anantineoplastic enzyme; a topoisomerase inhibitor; procarbazine;mitoxantrone; platinum coordination complexes such as cis-platin andcarboplatin; biological response modifiers; growth inhibitors;antihormonal therapeutic agents; leucovorin; tegafur; and haematopoieticgrowth factors.

Additional cytotoxic agents include, melphalan, hexamethyl melamine,thiotepa, cytarabin, idatrexate, trimetrexate, dacarbazine,L-asparaginase, camptothecin, topotecan, bicalutamide, flutamide,leuprolide, pyridobenzoindole derivatives, interferons, andinterleukins.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, microcrystalline cellulose, sodiumcrosscarmellose, corn starch, or alginic acid; binding agents, forexample starch, gelatin, polyvinyl-pyrrolidone or acacia, andlubricating agents, for example, magnesium stearate, stearic acid ortalc. The tablets may be uncoated or they may be coated by knowntechniques to mask the unpleasant taste of the drug or delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a watersoluble taste masking material such as hydroxypropyl-methylcellulose orhydroxypropyl-cellulose, or a time delay material such as ethylcellulose, cellulose acetate buryrate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with watersoluble carrier such as polyethyleneglycol or an oil medium, for examplepeanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethylene-oxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present. These compositions may be preserved by theaddition of an anti-oxidant such as ascorbic acid.

The pharmaceutical compositions of the invention may also be in the formof an oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring phosphatides, for example soy bean lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening, flavoring agents, preservatives and antioxidants.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative, flavoring and coloring agentsand antioxidant.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous solutions. Among the acceptable vehicles and solventsthat may be employed are water, Ringer's solution and isotonic sodiumchloride solution.

The sterile injectable preparation may also be a sterile injectableoil-in-water microemulsion where the active ingredient is dissolved inthe oily phase. For example, the active ingredient may be firstdissolved in a mixture of soybean oil and lecithin. The oil solutionthen introduced into a water and glycerol mixture and processed to forma microemulation.

The injectable solutions or microemulsions may be introduced into apatient's blood-stream by local bolus injection. Alternatively, it maybe advantageous to administer the solution or microemulsion in such away as to maintain a constant circulating concentration of the instantcompound. In order to maintain such a constant concentration, acontinuous intravenous delivery device may be utilized. An example ofsuch a device is the Deltec CADD-PLUS™ model 5400 intravenous pump.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension for intramuscular andsubcutaneous administration. This suspension may be formulated accordingto the known art using those suitable dispersing or wetting agents andsuspending agents which have been mentioned above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example as a solution in 1,3-butane diol. In addition, sterile,fixed oils are conventionally employed as a solvent or suspendingmedium. For this purpose any bland fixed oil may be employed includingsynthetic mono- or diglycerides. In addition, fatty acids such as oleicacid find use in the preparation of injectables.

Compounds of Formulas I and II may also be administered in the form of asuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials include cocoa butter, glycerinated gelatin,hydrogenated vegetable oils, mixtures of polyethylene glycols of variousmolecular weights and fatty acid esters of polyethylene glycol.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compound of Formula I are employed. (For purposesof this application, topical application shall include mouth washes andgargles.)

The compounds for the present invention can be administered inintranasal form via topical use of suitable intranasal vehicles anddelivery devices, or via transdermal routes, using those forms oftransdermal skin patches well known to those of ordinary skill in theart. To be administered in the form of a transdermal delivery system,the dosage administration will, of course, be continuous rather thanintermittent throughout the dosage regimen. Compounds of the presentinvention may also be delivered as a suppository employing bases such ascocoa butter, glycerinated gelatin, hydrogenated vegetable oils,mixtures of polyethylene glycols of various molecular weights and fattyacid esters of polyethylene glycol.

When a compound according to this invention is administered into a humansubject, the daily dosage will normally be determined by the prescribingphysician with the dosage generally varying according to the age,weight, sex and response of the individual patient, as well as theseverity of the patient's symptoms.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described above andthe other pharmaceutically active agent or treatment within its approveddosage range. Compounds of Formulas I and II may also be administeredsequentially with known anticancer or cytotoxic agents when acombination formulation is inappropriate. The invention is not limitedin the sequence of administration; compounds of Formulas I and II may beadministered either prior to or after administration of the knownanticancer or cytotoxic agent(s).

Assays

The pharmacological properties of the compounds of this invention may beconfirmed by a number of pharmacological assays. The exemplifiedpharmacological assays which follow have been carried out with thecompounds according to the invention and salts thereof.

Met Kinase Assay

Reagents Substrate Mix Final Concentration Stock Solution Tris-HCl, (1M,pH 7.4) 20 mM MnCl₂ (1M) 1 mM DTT(1M) 1 mM BSA (100 mg/ml) 0.1 mg/mlpolyGlu₄/tyr (10 mg/ml) 0.1 mg/mL ATP (1 mM) 1 μM γ-ATP (10 μCi/μl) 0.2μCi/ml

Buffer Enzyme mix 20 ul 1M DTT 4 ul GST/Met enzyme(3.2 mg/ml) = 10ng/rxn 200 ul 1M Tris-HCL, qs 12 ml Buffer pH 7.4 20 ul 100 mg/ml BSA qs20 ml H₂0

Incubation mixtures employed for the Met kinase assay contain thesynthetic substrate polyGlu:Tyr, (4:1), ATP, ATP-γ-³³P and buffercontaining Mn⁺⁺ and/or Mg⁺⁺, DTT, BSA, and Tris buffer. Reactions wereincubated for 60 minutes at 27° C. and stopped by the addition of coldtrichloroacetic acid (TCA) to a final concentration 4%. TCA precipitateswere collected onto GF/C unifilter plates (Packard Instrument Co.,Meriden, Conn.) using a Filtermate universal harvester (PackardInstrument Co., Meriden, Conn.) and the filters are quantitated using aTopCount 96-well liquid scintillation counter (Packard Instrument Co.,Meriden, Conn.). Dose response curves were generated to determine theconcentration required to inhibit 50% of kinase activity (IC₅₀).Compounds were dissolved at 10 mM in dimethyl sulfoxide (DMSO) andevaluated at six concentrations, each in quadruplicate. The finalconcentration of DMSO in the assay is 1%. IC₅₀ values were derived bynon-linear regression analysis and had a coefficient of variance(SD/mean, n=6)=16%.

Preferred compounds of the invention inhibit Met kinase with IC₅₀ valuesbetween 0.01 to 100 μM. The most preferred compounds have IC₅₀ values ofless than 0.5 μM.

Further subject matter of the invention also includes pharmaceuticalsfor use as described above including controlling cancer, inflammationand arthritis, which contain at least one compounds of Formulas I and IIas defined above or at least one of its pharmacologically acceptableacid addition salts, and the use of a compound of the Formulas I and IIas defined above for the preparation of a pharmaceutical having activityagainst proliferative diseases as described previously including againstcancer, inflammation and/or arthritis.

The following examples and preparations describe the manner and processof making and using the invention and are illustrative rather thanlimiting. It should be understood that there may be other embodimentswhich fall within the spirit and scope of the invention as defined bythe claims appended hereto.

EXAMPLES

The invention will now be further described by the following workingexamples, which are preferred embodiments of the invention. Allreactions were carried out with continuous magnetic stirring under anatmosphere of dry nitrogen or argon. All evaporations and concentrationswere carried out on a rotary evaporator under reduced pressure.Commercial reagents were used as received without additionalpurification. Solvents were commercial anhydrous grades and were usedwithout further drying or purification. Flash chromatography wasperformed using silica gel (EMerck Kieselgel 60, 0.040-0.060 mm).

Analytical Reverse Phase (RP)HPLC was performed using a Phenomenex LunaC18 S5 4.6 mm×50 mm column or a YMC S5 ODS 4.6×50 mm column. In eachcase a 4 min linear gradient (from 100% A: % 0 B to 0% A: 100% B) wasused with the following mobile phase system: A=90% H₂O/MeOH+0.2% H₃PO₄;B=90% MeOH/H₂O+0.2% H₃PO₄ at flow rate=4 mL/min and detection at 220 nm.

Preparative Reverse Phase (RP)HPLC was performed with a linear gradientelution using 10% methanol, 90% water, 0.1% TFA (solvent A) and 90%methanol, 10% water, 0.1% TFA (solvent B) and detection at 220 nm on oneof the following columns: A—Shimadzu S50DS-VP 20×100 mm column with aflow rate of 20 mL/min; B—YMC S5 ODS 30×100 mm column with a flow rateof 20 mL/min; C—Phenomonex 30×250 mm column with a flow rate of 10mL/min; D—YMC S5 ODS 20×250 mm column with a flow rate of 10 mL/min;E—YMC S10 ODS 50×500 mm column with a flow rate of 50 mL/min; or F—YMCS10DS 30×500 mm column with a flow rate of 20 mL/min.

All final products were characterized by ¹H NMR, RPHPLC, electrosprayionization (ESI MS) or atmospheric pressure ionization (API MS) massspectrometry. ¹H NMR spectra were obtained on either a 500 MHz JEOL or a400 MHz Bruker instrument. ¹³C NMR spectra were recorded at 100 or 125MHz. Field strengths are expressed in units of 6 (parts per million,ppm) relative to the solvent peaks, and peak multiplicities aredesignated as follows: s, singlet; d, doublet; dd, doublet of doublets;dm, doublet of multiplets; t, triplet; q, quartet; br s, broad singlet;m, multiplet.

The following abbreviations are used for commonly used reagents: Boc orBOC: t-butyl carbamate; Fmoc: 9H-fluorenylmethyl carbamate; TEA:triethylamine; NMM: N-methylmorpholine; Ms: methanesulfonyl; DIEA orDIPEA: diisopropylethylamine or Hunig's base; NMP:N-methylpyrrolidinone; BOP reagent:benzotriazol-1-yloxytris(trimethylamino)phosphonium hexafluorophosphate;DCC: 1,3-dicyclohexylcarbodiimide; EDCI:1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; RT or rt:room temperature; tR: retention time; h: hour(s); min: minute(s);PyBroP: bromotripyrrolidinophosphonium hexafluorophosphate; TBTU:O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate;DMAP: 4-N,N-dimethylaminopyridine; HOBt or HOBT: hydroxybenzotriazole;Na(OAc)₃BH: sodium triacetoxyborohydride; HOAc: acetic acid; TFA:trifluoroacetic acid; LiHMDS: lithium bis(trimethylsilyl)amide; DMSO:dimethyl sulfoxide; MeCN: acetonitrile; MeOH: methanol; EtOAc: ethylacetate; DMF: dimethyl formamide; THF: tetrahydrofuran; DCE:1,2-dichloroethane; Et₂O: diethyl ether; DCM: dichloromethane ormethylene chloride; m-CPBA: 4-chloroperoxybenzoic acid.

Example 1

N-(4-Fluorophenyl)-N-(4-(pyridin-4-yloxy)phenyl)malonamide

A) 4-(4-Aminophenoxy)pyridine

A solution of 4-chloropyridine hydrochloride (Aldrich, 3.0 g, 20.0 mmol)in dimethyl sulfoxide (40 mL) was treated with 4-aminophenol (Aldrich,2.1 g, 20.0 mmol) and sodium hydroxide pellets (2.0 g, 50.0 mmol) andthe mixture was heated at 100° C. for 18 h. The mixture was cooled toroom temperature, poured onto a mixture of ice-water (300 g) andextracted with Et₂O (3×150 mL). The combined extracts were washed withbrine, dried (MgSO₄) and concentrated to give the4-(4-aminophenoxy)aniline as a pale yellow solid (3.5 g, 94%). ¹H NMR(DMSO-d₆) δ 8.38 (dd, 2H, J=5.5, 1.5 Hz), 6.83-6.79 (m, 4H), 6.63-6.59(m, 2H), 5.13 (br s, 2H); MS (ESI⁺) m/z 187.2 (M+H)⁺.

B) 3-(4-Fluorophenylamino)-3-oxopropanoic acid

To a solution of ethyl 3-chloro-3-oxopropanoate (Aldrich, 5.0 mL, 40mmol) in methylene chloride (100 mL) at 0° C. was addeddiisopropylethylamine (8.4 mL, 48 mmol) followed by 4-fluoroaniline(Aldrich, 3.6 mL, 38 mmol). The reaction mixture was stirred at roomtemperature overnight and was then quenched with 100 mL of saturatedNaHCO₃ solution. The aqueous layer was extracted with chloroform (3×100mL). The combined organic extracts were dried over anhydrous Na₂SO₄ andconcentrated in vacuo to give the crude product as a yellow oil thatsolidified upon standing (10 g). ¹H NMR (CDCl₃) δ 9.30 (br s, 1H), 7.55(m, 2H), 7.05 (t, 2H, J=8.8 Hz), 4.28 (q, 2H, J=7.2 Hz), 3.49 (s, 2H),1.35 (t, 3H, J=7.1 Hz); MS (ESI⁺) m/z 226.11 (M+H)⁺.

The above ester was dissolved in 100 mL of ethanol and cooled to 0° C. 1N aq. NaOH solution (100 mL) was added and the reaction was stirred at0° C. for 1 h. The reaction was concentrated in vacuo to remove ethanol.The aqueous solution was extracted with EtOAc (50 mL) and was then madeacidic with 1N aq HCl solution. The aqueous solution was extracted withEtOAc (5×100 mL). The combined organic extracts were dried overanhydrous Na₂SO₄ and concentrated in vacuo to give the crude product asa yellow solid (6.31 g, 84%) which was used without furtherpurification. ¹H NMR (DMSO-d₆) δ 12.9 (br s, 1H), 10.3 (br s, 1H), 7.59(m, 2H), 7.16 (t, 2H, J=8.9 Hz), 3.34 (s, 2H); MS (ESI⁺) m/z 198.43(M+H)⁺.

C) N-(4-Fluorophenyl)-N-(4-(pyridin-4-yloxy)phenyl)malonamide

A solution of 4-(4-aminophenoxy)pyridine (93 mg, 0.50 mmol) in DMF wastreated with 3-(4-fluorophenylamino)-3-oxopropanoic acid (99 mg, 0.50mmol), DIPEA (113 μL, 0.65 mmol) and TBTU (209 mg, 0.65 mmol) and themixture was stirred at RT for 2 h. The mixture was concentrated toremove the DMF and the residue partitioned between EtOAc and saturatedsodium bicarbonate solution. The EtOAc phase was washed with saturatedsodium bicarbonate solution, brine, dried (MgSO₄) and concentrated togive the title compound as an off-white foam (140 mg, 76%). ¹H NMR(DMSO-d₆) δ 10.30 (s, 1H), 10.24 (s, 1H), 8.43 (dd, 2H, J=5.5, 1.5 Hz),7.70 (d, 2H, J=9.1 Hz), 7.63-7.60 (m, 2H), 7.17-7.14 (m, 4H), 6.89 (dd,2H, J=5.5, 1.5 Hz), 3.46 (s, 2H); MS (ESI⁺) m/z 365.9 (M+H)⁺.

Example 2

1-(4-(6-Chloropyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)thiourea

A) 4-Chloro-6-(2-fluoro-4-nitrophenoxy)pyrimidine

A mixture of 4,6-dichloropyrimidine (Aldrich, 0.74 g, 5.0 mmol),2-fluoro-4-nitrophenol (Aldrich, 0.79 g, 5.0 mmol) and DMF (10 ml) wastreated with potassium carbonate (0.72 g, 5.2 mmol) and heated at 80° C.for 3 h. The mixture was cooled, diluted with water and extracted withethyl acetate. The ethyl acetate extract was washed with brine, dried(MgSO₄), and concentrated to give the crude product as a yellow solid.The crude product was triturated with isopropyl ether to give4-chloro-6-(2-fluoro-4-nitrophenoxy)pyrimidine as a yellow solid (1.3 g,94%). ¹H NMR (DMSO-d₆) δ 8.80 (s, 1H), 8.51 (dd, 1H, J=8.6, 2.5 Hz),8.31 (d, 1H, J=9.1 Hz), 7.87 (d, 1H, J=9.1 Hz), 7.84 (s, 1H).

B) 4-Chloro-6-(2-amino-2-fluorophenoxy)pyrimidine

A solution of 4-chloro-6-(2-fluoro-4-nitrophenoxy)pyrimidine (1.3 g, 4.8mmol) in methanol (120 mL) was treated with Raney nickel (1.5 g, aqueousslurry) and the reaction mixture was stirred under a blanket of hydrogen(from a latex balloon) at RT for 3 h. The catalyst was filtered off, thefiltrate concentrated, and the residue partitioned between CH₂Cl₂ andwater. The methylene chloride phase was separated, dried (MgSO₄) andconcentrated. The crude product was purified by flash chromatography onsilica gel using 1-2% MeOH in CH₂Cl₂ as the eluent to give4-chloro-6-(2-amino-2-fluorophenoxy)pyrimidine as a white solid (600 mg,52%). ¹H NMR (DMSO-d₆) δ 8.64 (s, 1H), 7.39 (s, 1H), 6.97 (dd, 1H,J=8.8, 8.8 Hz), 6.46 (dd, 1H, J=13.1, 2.5 Hz), 6.38 (dd, 1H, J=8.6, 2.5Hz), 5.44 (br s, 2H); MS (ESI⁺) m/z 240.04 (M+H)⁺.

C)1-(4-(6-Chloropyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)thiourea

4-Fluorophenylacetyl chloride (Lancaster, 0.52 g, 3.0 mmol) was added toa mixture of NaSCN (0.27 g, 3.3 mmol) and EtOAc (12 mL) and theresulting mixture stirred at RT for 30 min. This mixture was added to asolution of 4-chloro-6-(2-amino-2-fluorophenoxy)pyrimidine in 1:1EtOAc/CH₂Cl₂ (5 ml) and the resulting mixture stirred at RT overnight.The mixture was concentrated and the residue partitioned betweenEtOAc/H₂O. The EtOAc phase was separated, washed with brine, dried(MgSO₄) and concentrated. The product was purified by flashchromatography using 10-35% EtOAc/hexanes as the eluent to give thetitle compound as a yellow crystalline solid (0.85 g, 65%). ¹H NMR(DMSO-d₆) δ 12.40 (s, 1H), 11.81 (s, 1H), 8.67 (s, 1H), 7.90 (dd, 1H,J=12.1, 2.0 Hz), 7.62 (s, 1H), 7.47-7.41 (m, 2H), 7.38-7.35 (m, 2H),7.17 (t, 2H, J=8.8 Hz), 3.81 (s, 2H); MS (ESI⁺) m/z 434.98 (M+H)⁺.

Example 3

1-(2-(4-Fluorophenyl)acetyl)-3-(4-(pyridin-4-yloxy)phenyl)thiourea

The title compound was prepared using 4-(4-aminophenoxy)pyridine(Compound A of Example 1) and a similar procedure outlined for thepreparation of Compound C of Example 2. Yield: 10%. ¹H NMR (CDCl₃) δ12.3 (s, 1H), 8.63 (s, 1H), 8.49, (d, 2H, J=6.2 Hz), 7.71 (d, 2H, J=8.9Hz), 7.31-7.27 (m, 2H), 7.14-7.09 (m, 4H), 6.90 (dd, 2H, J=4.8, 1.4 Hz),3.73 (s, 2H); MS (ESI⁺) m/z 382.2 (M+H)⁺.

Example 4

N¹-(4-(6-Chloropyrimidin-4-yloxy)-3-fluorophenyl)-N³-(4-fluorophenyl)malonamide

A solution of 4-chloro-6-(2-amino-2-fluorophenoxy)pyrimidine (29 mg,0.12 mmol, Compound B of Example 2),3-(4-fluorophenylamino)-3-oxopropanoic acid (26 mg, 0.13 mmol, CompoundB of Example 1) in DMF (1.5 mL) was treated with DIPEA (24 μl, 0.14mmol) and TBTU (46 mg, 0.14 mmol). The reaction mixture was stirred atRT overnight, diluted with EtOAc (25 mL), and the organic phase waswashed with brine (3×20 mL), dried (MgSO₄) and concentrated. The productwas purified by flash chromatography using 1-3% MeOH in CH₂Cl₂ as theeluent to give the title compound as a white solid (35 mg, 78%). ¹H NMR(DMSO-d₆) δ 10.49 (s, 1H), 10.25 (s, 1H), 8.65 (s, 1H), 7.78 (d, 1H,J=12.1 Hz), 7.63-7.57 (m, 3H), 7.40-7.34 (m, 2H), 7.16 (t, 2H, J=8.8Hz), 3.48 (s, 2H); MS (ESI⁺) m/z 419.21 (M+H)⁺.

Example 5

N⁴-(3-Fluoro-4-(6-(methylamino)pyrimidin-4-yloxy)phenyl)-N³-(4-fluorophenyl)malonamide

A solution ofN¹-(4-(6-chloropyrimidin-4-yloxy)-3-fluorophenyl)-N³-(4-fluorophenyl)malonamide(100 mg, 0.42 mmol, Example 4) in n-BuOH (3 mL) was treated with 2 Mmethylamine/THF (0.2 mL) and heated in a screw cap vial at 80° C. for 12h. The mixture was concentrated and the residue purified by preparativeHPLC using a gradient of MeOH—H₂O containing 0.1% TFA. The fractioncontaining the product was lyophilized to give the title compound as apale yellow solid (60 mg, 34%). ¹H NMR (DMSO-d₆) δ 10.58 (s, 1H), 10.36(br s, 2H), 8.19 (br s, 1H), 7.76 (d, 1H, J=12.1 Hz), 7.64-7.62 (m, 2H),7.36-7.27 (m, 2H), 7.15 (dd, 2H, J=8.8, 8.8 Hz), 5.95 (br s, 1H), 3.49(s, 2H), 2.80 (s, 3H); MS (ESI⁺) m/z 414.16 (M+H)⁺.

Example 6

tert-Butyl6-(2-fluoro-4-(3-(4-fluorophenylamino)-3-oxopropanamido)phenoxy)pyrimidin-4-ylcarbamate

A) N-(2,4,6-Trimethoxybenzyl)-6-chloropyrimidin-4-amine

A mixture of 4,6-dichloropyrimidine (Aldrich, 1.48 g, 10.0 mmol),2,4,6-trimethoxybenzylamine hydrochloride (2.33 g, 10.0 mmol), DIPEA(4.8 mL, 27.7 mmol), and n-BuOH (50 mL) was heated at 100° C. for 2 h.The mixture was cooled, diluted with water (200 mL) and the precipitatedproduct was collected by vacuum filtration on a Büchner funnel. Theproduct was washed with cold water, ether, and vacuum dried to give anoff-white solid (2.8 g, 90%). ¹H NMR (DMSO-d₆) δ 8.28 (s, 1H), 7.38 (s,1H), 6.49 (s, 1H), 6.25 (s, 2H), 4.34 (s, 2H), 3.77 (s, 9H).

B) 6-(2-Fluoro-4-nitrophenoxy)pyrimidin-4-amine

A mixture of N-(2,4,6-trimethoxybenzyl)-6-chloropyrimidin-4-amine (2.2g, 7.11 mmol), 2-fluoro-4-nitrophenol (1.1 g, 7.0 mmol), and2-methoxyethyl ether (50 mL) was heated at 160° C. for 60 h. Thereaction mixture was cooled to RT and poured into H₂O (200 mL). Thesolid was collected, washed with 2 M aqueous Na₂CO₃ and H₂O, and thenvacuum dried on a Büchner funnel. The crude product was treated with TFA(20 mL) in dioxane (40 mL) and stirred at RT for 4 h. The reactionmixture was concentrated, the residue partitioned between EtOAc andsaturated NaHCO₃ solution. The EtOAc phase was separated, dried (MgSO₄),concentrated and the crude product purified by flash chromatographyusing 1-2% MeOH in CH₂Cl₂ as the eluent to give6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-amine (440 mg, 31%). ¹H NMR(DMSO-d₆) δ 8.31 (dd, 1H, J=10.4, 2.5 Hz), 8.14 (dd, 1H, J=9.8, 2.0 Hz),8.04 (s, 1H), 7.61 (dd, 1H, J=8.3, 8.3 Hz), 7.07 (s, 2H), 6.02 (s, 1H);MS (ESI⁺) m/z 251.15 (M+H)⁺.

C) tert-Butyl 6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-ylcarbamate

A mixture of 6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-amine (439 mg, 1.2mmol), BOC₂O (261 mg, 1.2 mmol), DMAP (10 mg), and THF (10 mL) wasstirred at RT for 1 h then concentrated in vacuo to give the crudeproduct. The product was purified by flash chromatography using 1-2%MeOH in CH₂Cl₂ as the eluent to give tert-butyl6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-ylcarbamate as a white solid (110mg, 26%). ¹H NMR (DMSO-d₆) δ 10.59 (s, 1H), 8.39 (dd, 1H, J=8.8, 1.1Hz), 8.32 (dd, 1H, J=10.3, 2.4 Hz), 8.15 (ddd, 1H, J=9.1, 2.5, 1.0 Hz),7.67 (dd, 1H, J=8.8, 8.8 Hz), 7.45 (s, 1H), 1.44 (s, 9H); MS (ESI⁻) m/z349.08 (M−H).

D) tert-Butyl 6-(4-amino-2-fluorophenoxy)pyrimidin-4-ylcarbamate

A solution of tert-butyl6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-ylcarbamate (11 mg, 0.031 mmol)in MeOH (2 mL) was treated with PtO₂ and the reaction mixture wasstirred under a blanket of hydrogen (from a latex balloon) for 2 h. Thecatalyst was filtered off and the filtrate concentrated to givetert-butyl 6-(4-amino-2-fluorophenoxy)pyrimidin-4-ylcarbamate (8 mg,81%). ¹H NMR (DMSO-d₆) δ 10.62 (s, 1H), 8.43 (d, 1H, J=2.5 Hz), 8.36(dd, 1H, J=9.8, 2.5 Hz), 8.36 (dd, 1H, J=9.8, 2.5 Hz), 8.20-8.17 (m,1H), 7.71 (dd, 1H, J=8.8, 8.8 Hz), 7.49 (s, 1H), 1.48 (s, 9H).

E) tert-Butyl6-(2-fluoro-4-(3-(4-fluorophenylamino)-3-oxopropanamido)phenoxy)pyrimidin-4-ylcarbamate

The title compound was prepared from tert-butyl6-(4-amino-2-fluorophenoxy)pyrimidin-4-ylcarbamate (8 mg, 0.025 mmol)and (4-fluorophenylamino)-3-oxopropanoic acid (6 mg, 0.031 mmol,Compound B of Example 1), TBTU (11 mg, 0.034 mmol), and DIPEA (6 μL,0.030 mmol) using a similar procedure described for the preparation ofCompound C, Example 1. Flash chromatography using 1-1.5% MeOH in CH₂Cl₂as the eluent gave the title compound as a white solid (10 mg, 80%). ¹HNMR (DMSO-d₆) δ 10.48 (s, 1H), 10.46 (s, 1H), 10.25 (s, 1H), 8.39 (s,1H), 7.74-7.77 (m, 1H), 7.62 (d, 1H, J=5.5 Hz), 7.61 (d, 1H, J=4.9 Hz),7.36-7.30 (m, 2H), 7.17-7.13 (m, 2H), 3.48 (s, 2H), 1.46 (s, 9H); MS(ESI⁺) m/z 500.12 (M+H)⁺.

Example 7

tert-Butyl6-(2-fluoro-4-(3-(4-fluorophenylamino)-3-oxopropanamido)phenoxy)pyrimidin-4-yl(methyl)carbamate

A) tert-Butyl 6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-yl(methyl)carbamate

A solution of tert-butyl6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-ylcarbamate (Compound C ofExample 6, 44 mg, 0.13 mmol) in anhydrous DMF (1 mL) was cooled in anice bath and treated with 60% NaH (44 mg, 0.16 mmol) and stirred at thesame temperature for 30 minutes. The reaction mixture was treated withiodomethane (10 μL, 0.15 mmol) and stirred at 0-5° C. for 10 min. Thereaction mixture was allowed to warm to room temperature and stirred for30 min. The mixture was diluted with H₂O (10 mL) and extracted withEtOAc (2×10 mL). The combined extracts were dried (MgSO₄) andconcentrated in vacuo to give the product (35 mg, 74%) as a pale yellowsolid. ¹H NMR (DMSO-d₆) δ 8.57 (d, 1H, J=1.1 Hz), 8.37 (dd, 1H, J=9.8,3.0 Hz), 8.19 (ddd, 1H, J=9.1, 2.5, 1.0 Hz), 7.71 (dd, 1H, J=8.8, 8.8Hz), 7.66 (s, 1H), 3.38 (s, 3H), 1.51 (s, 9H).

B) tert-Butyl 6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl(methyl)carbamate

A mixture of tert-butyl6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-yl(methyl)carbamate in 1:1EtOH/MeOH (2 mL) was treated with PtO₂ (10 mg) and the reaction mixturewas stirred under a blanket of H₂ (from a latex balloon) for 2 h. Thereaction mixture was filtered and concentrated to give the desiredproduct (30 mg, 75%) as a light brown solid. MS (ESI⁺) m/z 365.13(M+H)⁺.

C) tert-Butyl6-(2-fluoro-4-(3-(4-fluorophenylamino)-3-oxopropanamido)phenoxy)pyrimidin-4-yl(methyl)carbamate

The title compound was prepared from tert-butyl6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl(methyl)carbamate (30 mg, 0.068mmol), 4-fluorophenylacetyl chloride (Lancaster, 15 mg, 0.088 mmol) andNaSCN (9 mg, 0.11 mmol) in EtOAc/CH₂Cl₂ using a similar proceduredescribed for the preparation of Compound C of Example 2. Flashchromatography on SiO₂ using 1-40% EtOAc in hexanes as the eluent gavethe title compound (30 mg, 83%) as a white solid. ¹H NMR (DMSO-d₆) δ12.40 (s, 1H), 11.79 (s, 1H), 8.55 (s, 1H), 7.86 (dd, 1H, J=12.1, 2.5Hz), 7.54 (d, 1H, J=1.1 Hz), 7.45-7.35 (m, 4H), 7.20-7.14 (ddd, 2H,J=8.8, 8.8, 2.1 Hz), 3.81 (s, 2H), 3.36 (s, 3H), 1.49 (s, 9H); MS (ESI⁺)m/z 530.09 (M+H)⁺.

Example 8

1-(3-Fluoro-4-(6-(methylamino)pyrimidin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)thiourea

tert-Butyl6-(2-fluoro-4-(3-(4-fluorophenylamino)-3-oxopropanamido)phenoxy)pyrimidin-4-yl(methyl)carbamate(Example 7, 25 mg, 0.047 mmol) was treated with 4 M HCl in 1,4-dioxane(3 mL), stirred at RT for 4 h and concentrated in vacuo. The residue waspartitioned between saturated aq. NaHCO₃ solution and EtOAc. The EtOAcphase was separated, dried (MgSO₄) and concentrated in vacuo. Flashchromatography on SiO₂ using 1% MeOH in CH₂Cl₂ as the eluent gave thetitle compound (10 mg, 50%) as a white solid. ¹H NMR (DMSO-d₆) δ 12.37(s, 1H), 11.77 (s, 1H), 8.09 (s, 1H), 7.82 (d, 1H, J=11.6 Hz), 7.41-7.35(m, 5H), 7.32-7.28 (m, 1H), 7.19-7.14 (m, 2H), 3.81 (s, 2H), 2.78 (s,3H); MS (ESI⁺) m/z 430.07 (M+H)⁺.

Example 9

1-(4-(6-Aminopyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)thiourea

A)6-(N,N-di-tert-Butyloxycarbonyl)amino-4-(2-fluoro-4-nitrophenoxy)pyrimidine

A mixture of 6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-amine (Compound B ofExample 6, 150 mg, 0.60 mmol), BOC₂O (275 mg, 1.26 mmol), DMAP (5 mg),and THF (20 mL) was stirred at RT for 2.5 h. The reaction mixture wasconcentrated in vacuo to give the crude product. Flash chromatography onSiO₂ using 5-15% EtOAc in hexanes as the eluent gave the title compound(180 mg, 67%) as white solid. ¹H NMR (DMSO-d₆) δ 8.62 (d, 1H, J=1.0 Hz),8.42-8.39 (m, 1H), 8.21 (ddd, 1H, J=9.1, 2.5, 1.0 Hz), 7.77 (dd, 1H,J=8.8, 8.8 Hz), 7.49 (d, 1H, J=1.1 Hz), 1.49 (s, 18H); MS (ESI⁺) m/z451.12 (M+H)⁺.

B)6-(N,N-di-tert-Butyloxycarbonyl)amino-4-(4-amino-2-fluorophenoxy)pyrimidine

A mixture of the6-(N,N-di-tert-butyloxycarbonyl)amino-4-(2-fluoro-4-nitrophenoxy)pyrimidine(175 mg, 0.38 mmol) in toluene (5 mL) and MeOH (3 mL) was treated withPtO₂ (35 mg) and the reaction mixture was stirred under a blanket of H₂(from a latex balloon) for 15 h. The catalyst was filtered off, thefiltrate concentrated in vacuo and the residue was purified by flashchromatography on SiO₂ using 1-10% MeOH in CH₂Cl₂ as the eluent to givethe product (110 mg, 68%) as a white solid. ¹H NMR (DMSO-d₆) δ 8.56 (s,1H), 7.17 (s, 1H), 6.97 (dd, 1H, J=8.8, 8.8 Hz), 6.46 (dd, 1H, J=12.6,2.5 Hz), 6.38 (dd, 1H, J=8.8, 2.5 Hz), 5.40 (s, 2H), 1.89 (s, 18H).

C) 1-(4-(N,N-di-tert-Butyloxycarbonyl6-aminopyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)thiourea

The title compound was prepared from6-(N,N-di-tert-butyloxycarbonyl)amino-4-(4-amino-2-fluorophenoxy)pyrimidine(20 mg, 0.048 mmol), 4-fluorophenylacetyl chloride (Lancaster, 10 mg,0.062 mmol), and NaSCN (95 mg, 0.062 mmol) in EtOAc/CH₂Cl₂ using asimilar procedure described for the preparation of Compound C of Example2. Flash chromatography on SiO₂ using 10-20% EtOAc in hexanes as theeluent gave the title compound (23 mg, 77%) as a white solid. ¹H NMR(DMSO-d₆) δ 12.40 (s, 1H), 11.79 (s, 1H), 8.59 (s, 1H), 7.88 (dd, 1H,J=12.5, 1.8 Hz), 7.46-7.41 (m, 2H), 7.38-7.35 (m, 3H), 7.17 (dd, 2H,J=8.8, 8.8 Hz), 3.81 (s, 2H), 1.47 (s, 18H); MS (ESI⁺) m/z 616.12(M+H)⁺.

D)1-(4-(6-Aminopyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)thiourea

A mixture of 1-(4-(N,N-di-tert-butylcarbonyl6-aminopyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)thiourea(18 mg, 0.029 mmol) and 4 M HCl in dioxane (1.5 mL) was stirred at RTfor 18 h and then concentrated to give the crude product. The crudeproduct was partitioned between EtOAc and saturated aq. NaHCO₃ solution.The EtOAc phase separated, dried (MgSO₄), concentrated in vacuo and theresidue was purified by flash chromatography on SiO₂ using 1-2% MeOH inCH₂Cl₂ to give the title compound (12 mg, 99%) as a white solid. ¹H NMR(DMSO-d₆) δ 12.38 (s, 1H), 11.77 (s, 1H), 8.05 (s, 1H), 7.83 (dd, 1H,J=12.3, 1.8 Hz), 7.41-7.35 (m, 3H), 7.31 (dd, 2H, J=8.8, 8.8 Hz), 7.17(t, 1H, J=8.8 Hz), 7.02 (s, 2H), 5.89 (s, 1H), 3.81 (s, 2H); MS (ESI⁺)m/z 416.06 (M+H)⁺.

Example 10

N¹-1-(4-(6-Aminopyrimidin-4-yloxy)-3-fluorophenyl)-N³-(4-fluorophenyl)malonamide

A) N¹-(4-(N,N-di-tert-Butylcarbonyl16-aminopyrimidin-4-yloxy)-3-fluorophenyl)-N³-(4-fluorophenyl)malonamide

The title compound was prepared from a mixture of6-(N,N-di-tert-butyloxycarbonyl)amino-4-(4-amino-2-fluorophenoxy)pyrimidine(Compound B of Example 9, 20 mg, 0.048 mmol),3-(4-fluorophenylamino)-3-oxopropanoic (Compound B of Example 1, 14 mg,0.072 mmol), DIPEA (12 μL, 0.069 mmol) in DMF using a similar proceduredescribed for the preparation of Compound C of Example 1. Flashchromatography on SiO₂ using 15-50% EtOAc in hexanes as the eluent gavethe title compound (23 mg, 80%) as a white solid. ¹H NMR (DMSO-d₆) δ10.47 (s, 1H), 10.24 (s, 1H), 8.58 (d, 1H, J=1 Hz), 7.77 (dd, 1H,J=12.9, 1.8 Hz), 7.63-7.60 (m, 2H), 7.37-7.36 (m, 2H), 7.32 (s, 1H),7.15 (t, 2H, J=8.8 Hz), 1.47 (s, 18H); MS (ESI⁺) m/z 600.17 (M+H)⁺.

B)N¹-(4-(6-Aminopyrimidin-4-yloxy)-3-fluorophenyl)-N³-(4-fluorophenyl)malonamide

The title compound was prepared from N-1-(4-(N,N-di-tert-butylcarbonyl6-aminopyrimidin-4-yloxy)-3-fluorophenyl)-N-3-(4-fluorophenyl)malonamide(20 mg, 0.032 mmol) using a similar procedure described for thepreparation of Compound D of Example 9 to give the title compound (13mg, 98%) as a white solid. ¹H NMR (DMSO-d₆) δ 10.42 (s, 1H), 10.24 (s,1H), 8.03 (s, 1H), 7.73 (d, 1H, J=11.0 Hz), 7.61 (dd, 2H, J=9.2, 4.9Hz), 7.33-7.30 (m, 1H), 7.28-7.23 (m, 1H), 7.18-7.13 (m, 2H), 6.89 (s,2H), 5.80 (s, 1H), 3.47 (s, 2H); MS (ESI⁺) m/z 400.09 (M+H)⁺.

Example 11

1-(4-(6-(4-Methoxybenzylamino)pyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea

A) N-(4-Methoxybenzyl)-6-chloropyrimidin-4-amine

A mixture of 4,6-dichloropyrimidine (Aldrich, 3.6 g, 24.2 mmol),4-methoxybenzylamine (2.7 g, 19.7 mmol), DIPEA (5 ml, 28.8 mmol), andn-BuOH was heated at reflux for 3 h. The mixture was concentrated andthe residue treated with H₂O (150 mL) and EtOAc (175 mL). The EtOAcphase was separated, washed with saturated aq. NaHCO₃ solution andbrine, dried (MgSO₄), and concentrated to give the title compound (4.5g) which was used without further purification. ¹H NMR (DMSO-d₆) δ 8.29(s, 1H), 8.13 (br s, 1H), 7.25 (d, 2H, J=8.2 Hz), 6.90 (d, 2H, J=8.2Hz), 6.56 (s, 1H), 4.48 (s, 2H), 3.75 (s, 3H).

B) N-(4-Methoxybenzyl)-6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-amine

A mixture of N-(4-methoxybenzyl)-6-chloropyrimidin-4-amine (2.3 g, 9.2mmol), 2-fluoro-4-nitrophenol (1.45 g, 9.2 mmol), DIPEA (15 mL), and2-methoxyethyl ether (75 mL) was heated at 160° C. in a sealed pressurebottle for 50 h. The mixture was cooled, poured onto crushed ice (200g), treated with EtOAc (200 mL). After vigorously stirring for 10 min,the insoluble material was filtered off. The EtOAc phase was washed withsaturated aq. Na₂CO₃ solution (100 mL), brine (3×100 mL), dried (MgSO₄)and concentrated in vacuo. The gummy solid obtained was triturated withisopropyl ether to give the title compound (1.75 g, 76%) as a brownsolid. ¹H NMR (DMSO-d₆) δ 8.32 (dd, 1H, J=10.2, 2.0 Hz), 8.15 (d, 2H,J=9.2 Hz), 8.05 (br s, 1H), 7.61 (dd, 1H, J=8.4, 8.4 Hz), 7.26 (d, 2H,J=8.5 Hz), 6.91 (d, 2H, J=8.5 Hz), 6.14 (br s, 1H), 4.48 (br s, 2H),3.74 (s, 3H).

C) N-(4-Methoxybenzyl)-6-(4-amino-2-fluorophenoxy)pyrimidin-4-amine

A solution ofN-(4-methoxybenzyl)-6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-amine (150mg, 0.41 mmol) in 1:1 MeOH/THF (20 mL) was treated with ammoniumchloride (0.22 g, 4.1 mmol), and zinc dust (<20 microns, 0.27 g, 4.2mmol). The reaction mixture was stirred at RT for 1 h. An additionalportion of zinc dust (150 mg) was added to the mixture and the reactionmixture was stirred at RT for 1 h and heated at 70° C. for 20 min. Themixture was filtered to remove the inorganic solids, concentrated invacuo, and the residue partitioned between EtOAc and brine. The EtOAcphase was separated, washed with brine, dried (MgSO₄) and concentratedin vacuo to give the title compound (145 mg, 99%). ¹H NMR (DMSO-d₆) δ8.10 (br s, 1H), 7.76 (br s, 1H), 7.21 (d, 2H, J=8.6 Hz), 6.88 (d, 3H,J=8.6 Hz), 6.44 (dd, 1H, J=12.7, 2.0 Hz), 6.36 (dd, 1H, J=8.3, 2.3 Hz),5.79 (s, 1H), 4.41 (br s, 2H), 3.73 (s, 3H); MS (ESI⁺) m/z 341.18(M+H)⁺.

D) 2-(4-Fluorophenyl)acetyl isocyanate

Silver cyanate (0.912 g, 6.08 mmol, 1.05 eq) was added to a solution of4-fluorophenylacetyl chloride (Lancaster, 0.794 ml, 5.79 mmol, 1.0 eq)in toluene (16 ml) at room temperature. The reaction mixture wasshielded from light and heated to reflux. After 60 minutes, the mixturewas cooled to room temperature and filtered (Acrodisc, PTFE 0.2 μM) togive a 0.36 M solution of 2-(4-fluorophenyl)acetyl isocyanate intoluene, which was used without further purification.

E)1-(4-(6-(4-Methoxybenzylamino)pyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea

A solution ofN-(4-methoxybenzyl)-6-(4-amino-2-fluorophenoxy)pyrimidin-4-amine (88 mg,0.26 mmol) in THF (2 mL) was treated with 0.36 M2-(4-fluorophenyl)acetyl isocyanate in toluene (0.72 mL, 0.26 mmol) andthe reaction mixture was stirred at RT for 1 h. The mixture wasconcentrated in vacuo and the solid obtained was triturated withisopropyl ether to give the title compound (125 mg, 93%) as an off-whitesolid. ¹H NMR (DMSO-d₆) δ 11.00 (s, 1H), 10.50 (s, 1H), 8.09 (s, 1H),7.85 (br s, 0.5H), 7.66 (d, 1H, J=12.6 Hz), 7.36-7.15 (m, 9.5H), 6.88(d, 1H, J=8.1 Hz), 5.91 (s, 1H), 4.42 (br s, 2H), 3.72 (s, 2H), 3.71 (s,3H); MS (ESI⁺) m/z 520.14 (M+H)⁺.

Example 12

N¹-(4-(6-(4-Methoxybenzylamino)pyrimidin-4-yloxy)-3-fluorophenyl)-N-3-(4-fluorophenyl)malonamide

The title compound was prepared fromN-(4-methoxybenzyl)-6-(4-amino-2-fluorophenoxy)pyrimidin-4-amine(Compound C of Example 11, 200 mg, 0.59 mmol),3-(4-fluorophenylamino)-3-oxopropanoic acid (Compound B of Example 1,128 mg, 0.65 mmol), TBTU (228 mg, 0.71 mmol), and DIPEA (123 μL, 0.71mmol) in DMF using a similar procedure described for the preparation ofCompound C of Example 1. The crude product was purified by triturationwith isopropyl ether to give the title compound (250 mg, 82%) as anoff-white solid. ¹H NMR (DMSO-d₆) δ 10.43 (s, 1H), 10.25 (s, 1H), 8.09(s, 1H), 7.85 (s, 1H), 7.72 (dd, 1H, J=9.1, 5.0 Hz), 7.62 (dd, 2H,J=8.8, 5.0 Hz), 7.31-7.21 (m, 4H), 7.15 (dd, 2H, J=8.8, 8.8 Hz), 6.88(m, 2H), 5.90 (s, 1H), 4.42 (br s, 2H), 3.71 (s, 3H), 3.46 (s, 2H); MS(ESI⁺) m/z 520.14 (M+H)⁺.

Example 13

1-(4-(6-Aminopyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea

A) N-(3-Fluoro-4-hydroxyphenyl)acetamide

The title compound was prepared from the commercially available2-fluoro-4-nitrophenol according the procedure of Burckhalter, J. H. etal. (J. Am. Chem. Soc. 1948, 70, 1363). Nitrophenol (5.73 g, 36.5 mmol)and acetic anhydride (3.72 g, 36.5 mmol) were dissolved in acetic acid(20 mL) and PtO₂ (150 mg) was then added. The reaction mixture wasshaken under H₂ atmosphere (50 psi) at RT for 24 h. The precipitatewhich formed was collected by vacuum filtration and the filter paper waswashed with acetic acid (25 mL). The combined filtrate and washing wasconcentrated in vacuo to give the title compound (2.0 g). The solid thatremained on the filter paper was treated with MeOH to dissolve theproduct and the Pt₂O filtered off. The filtrate was concentrated invacuo and the solid obtained was triturated with 1:1 EtOAc/hexanes (200mL) to give a second crop of the title compound (1.8 g, 62% overall). ¹HNMR (DMSO-d₆) δ 9.83 (s, 1H), 9.51 (s, 1H), 7.50 (dd, 1H, J=13.6, 2.5Hz), 7.03 (d, 1H, J=8.5 Hz), 6.84 (dd, 1H, J=9.3, 9.3 Hz), 1.98 (s, 3H);MS (ESI⁺) m/z 170.23 (M+H)⁺.

B) N-(4-(6-Chloropyrimidin-4-yloxy)-3-fluorophenyl)acetamide

A mixture of 4,6-dichloropyrimidine (1.50 g, 10.0 mmol),N-(3-fluoro-4-hydroxyphenyl)acetamide (1.70 g, 10.0 mmol), K₂CO₃ (1.8 g,13.0 mmol), and DMF (15 mL) was heated at 70° C. for 1.5 h. The mixturewas concentrated to half its original volume and cooled in an ice bath.The mixture was treated with H₂O (100 mL) to precipitate the productwhich was collected by vacuum filtration. The product was washed withH₂O and vacuum dried on the funnel overnight to give the title compound(2.0 g, 71%) as a gray solid. ¹H NMR (DMSO-d₆) δ 10.26 (s, 1H), 8.67 (s,1H), 7.78 (dd, 1H, J=12.6, 2.0 Hz), 7.56 (s, 1H), 7.37-7.30 (m, 2H),2.08 (s, 3H); MS (ESI⁺) m/z 282.10 (M+H)⁺.

C) N-(4-(6-Aminopyrimidin-4-yloxy)-3-fluorophenyl)acetamide

A mixture of N-(4-(6-aminopyrimidin-4-yloxy)-3-fluorophenyl)acetamide(1.0 g, 3.5 mmol) and ca. 7 M NH₃ in MeOH (5 mL) was heated at 100° C.in a sealed pressure bottle for 2 h. The mixture was concentrated invacuo and the residue partitioned between EtOAc and saturated aq. NaHCO₃solution. The EtOAc phase was separated, washed with brine, dried(MgSO₄) and concentrated. Flash chromatography on SiO₂ using first 50%EtOAc in hexanes then 5% MeOH in CH₂Cl₂ as eluents gave the titlecompound (175 mg, 20%) as a brown solid. ¹H NMR (DMSO-d₆) δ 10.17 (s,1H), 8.02 (s, 1H), 7.70 (dd, 1H, J=13.2, 2.2 Hz), 7.26 (dd, 1H, J=8.8,2.2 Hz), 7.22 (dd, 1H, J=8.8, 8.8 Hz), 6.89 (br s, 2H), 2.05 (s, 3H); MS(ESI⁺) m/z 263.15 (M+H)⁺.

D) 6-(4-Amino-2-fluorophenoxy)pyrimidin-4-amine

A mixture of N-(4-(6-aminopyrimidin-4-yloxy)-3-fluorophenyl)acetamide(175 mg, 0.67 mmol), 1 M HCl (6 mL), and MeOH (2 mL) was heated atreflux for 3 h. The reaction mixture was cooled, made basic (pH 8) withaqueous Na₂CO₃ solution and extracted with EtOAc (2×25 mL). The combinedextracts were dried (MgSO₄) and concentrated in vacuo to give the titlecompound (140 mg, 96%) as a brown solid. ¹H NMR (DMSO-d₆) δ 8.02 (s,1H), 6.89 (dd, 1H, J=9.0, 9.0 Hz), 6.80 (br s, 2H), 6.43 (dd, 1H,J=12.7, 2.8 Hz), 6.35 (dd, 1H, J=8.8, 2.2 Hz), 5.67 (s, 1H), 5.34 (br s,2H).

E)1-(4-(6-Aminopyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea

The title compound was prepared from6-(4-amino-2-fluorophenoxy)pyrimidin-4-amine (92 mg, 0.42 mmol) and 0.36M 2-(4-fluorophenyl)acetyl isocyanate in toluene (Compound D of Example11, 1.3 mL, 0.45 mmol) in THF as described above for Example 11. Thecrude product was purified by trituration using 1:1 EtOH/H₂O followed byabsolute EtOH. The product was vacuum dried to give the title compound(100 mg, 60%). A second, slightly less pure crop of the product (45 mg,27%) was obtained by extracting the combined filtrates and washing withEtOAc. ¹H NMR (DMSO-d₆) δ 10.99 (s, 1H), 10.50 (s, 1H), 8.01 (s, 1H),7.65 (dd, 1H, J=12.6, 2.1 Hz), 7.33 (dd, 2H, J=8.1, 6.0 Hz), 7.28 (dd,1H, J=8.6, 2.0 Hz), 7.22 (dd, 1H, J=8.8, 8.8 Hz), 7.17-7.12 (m, 2H),6.89 (br s, 2H), 5.80 (s, 1H), 3.71 (s, 2H); MS (ESI⁺) m/z 400.09(M+H)⁺.

Example 14

N¹-(4-(2-(4-Methoxybenzylamino)pyrimidin-4-yloxy)-3-fluorophenyl)-N³-(4-fluorophenyl)malonamide

A) 2-Chloro-4-(2-fluoro-4-nitrophenoxy)pyrimidine

A mixture of 2,4-dichloropyrimidine (Aldrich, 0.74 g, 5.0 mmol),2-fluoro-4-nitrophenol (Avacado, 0.79 g, 5.0 mmol), K₂CO₃ (0.76 g, 5.5mmol), and DMF (50 mL) was heated at 100° C. for 2 h. The mixture wascooled and diluted with saturated NaHCO₃ solution (100 mL) and extractedwith EtOAc. The EtOAc extract was washed with brine, dried (MgSO₄) andconcentrated in vacuo to give a mixture of the 2-phenoxy- and4-phenoxypyrimidine regioisomers as a yellow solid. The regioisomerswere separated by flash chromatography using 10-40% EtOAc in hexanes asthe eluent to give the title compound (0.71 g, 53%) as a white solid. ¹HNMR (DMSO-d₆) δ 8.76 (dd, 1H, J=6.0, 1.6 Hz), 8.43 (dt, 1H, J=9.8, 2.2Hz), 8.23 (dd, 1H, J=8.8, 1.6 Hz), 7.80 (dt, 1H, J=9.8, 2.2 Hz), 7.48(dd, 1H, J=6.0, 2.2 Hz).

B) N-(4-Methoxybenzyl)-4-(2-fluoro-4-nitrophenoxy)pyrimidin-2-amine

A mixture of 2-chloro-4-(2-fluoro-4-nitrophenoxy)pyrimidine (0.66 g,2.44 mmol), 4-methoxybenzylamine (0.34 g, 3.45 mmol), K₂CO₃ (0.37 g,2.66 mmol), and DMF (15 mL) was heated at 100° C. for 1 h. The mixturewas cooled, diluted with H₂O (100 mL) and extracted with EtOAc (100 mL).The organic phase was washed twice each with saturated NaHCO₃ solutionand brine. The organics were dried (MgSO₄) and concentrated to give thecrude product. Flash chromatography on SiO₂ using 1-3% MeOH in CH₂Cl₂ asthe eluent gave the title compound (275 mg, 29%) as a pale yellow solid.¹H NMR (DMSO-d₆) δ 8.40-8.21 (m, 2H), 8.16 (dd, 1H, J=8.8, 1.7 Hz), 7.98(br s, 0.5H), 7.73-7.55 (m, 1.5H), 7.16 (br s, 1H), 6.85-6.71 (m, 3H),6.37 (s, 1H), 4.43 (br s, 1H), 3.95 (br s, 1H), 3.69 (s, 3H).

C) N-(4-Methoxybenzyl)-4-(4-amino-2-fluorophenoxy)pyrimidin-2-amine

The title compound was obtained by the reduction ofN-(4-methoxybenzyl)-4-(2-fluoro-4-nitrophenoxy)pyrimidin-2-amine (270mg, 0.73 mmol) with zinc dust (475 mg, 7.3 mmol) and NH₄Cl (387 mg, 7.3mmol) in 1:1 THF/MeOH (20 mL) using a similar procedure described forCompound C of Example 11. Flash chromatography on SiO₂ using 1-3% MeOHin CH₂Cl₂ as the eluent gave the title compound (235 mg, 95%) as a brownfilm. ¹H NMR (DMSO-d₆) δ 8.01 (s, 1H), 7.65 (br s, 0.5H), 7.49 (br s,0.5H), 7.08 (br s, 1H), 6.83 (br s, 2H), 6.81 (m, 1H), 6.69 (br s, 2H),6.39 (br s, 0.5H), 6.31 (br s, 0.5H), 6.01 (m, 1H), 5.26 (br s, 2H),4.24 (br s, 1H), 3.95 (br s, 1H), 3.61 (s, 3H); MS (ESI⁺) m/z 341.16(M+H)⁺.

D)N¹-(4-(2-(4-Methoxybenzylamino)pyrimidin-4-yloxy)-3-fluorophenyl)-N³-(4-fluorophenyl)malonamide

The title compound was obtained fromN-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)pyrimidin-2-amine (34 mg,0.10 mmol), 3-(4-fluorophenylamino)-3-oxopropanoic acid (Compound B ofExample 1, 22 mg, 0.11 mmol), TBTU (39 mg, 0.12 mmol) and DIPEA (23 mL,0.17 mmol) using a similar procedure described for the preparation ofCompound C of Example 1. The crude product was triturated with 3:1isopropyl ether/EtOAc to give the title compound (35 mg, 61%) as anoff-white solid. ¹H NMR (DMSO-d₆) δ 10.47 (br s, 1H), 10.26 (s, 1H),8.15 (s, 1H), 7.77 (m, 3H), 7.61 (m, 2H), 7.35-7.25 (m, 2H), 7.15 (dd,2H, J=8.8, 8.8 Hz), 6.81-6.73 (m, 2H), 6.24 (s, 1H), 4.32 (br s, 1H),3.96 (br s, 1H), 3.68 (s, 1H), 3.48 (s, 2H); MS (ESI⁺) m/z 520.14(M+H)⁺.

Example 15

1-(4-(2-(4-Methoxybenzylamino)pyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea

A solution ofN-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)pyrimidin-2-amine(Compound C of Example 14, 34 mg, 0.10 mmol) in THF (1 ml) was treatedwith 0.36 M 2-(4-fluorophenyl)acetyl isocyanate in toluene (Compound Dof Example 11, 0.31 mL, 0.11 mmol) and the mixture stirred at RT for 1h. The mixture was concentrated in vacuo and the solid obtained wastriturated first with 3:1 isopropyl ether/EtOAc and then CH₂Cl₂ to givethe title compound (32 mg, 62%) as an off-white solid. ¹H NMR (DMSO-d₆)δ 10.47 (s, 1H), 10.26 (s, 1H), 8.15 (s, 1H), 7.76 (d, 1H, J=12.6 Hz),7.61 (dd, 3H, J=9.1, 5.0 Hz), 7.29 (s, 2H), 7.31-7.21 (m, 3H), 6.81 (s,3H), 6.24 (s, 1H), 4.32 (s, 1H), 3.96 (s, 1H), 3.68 (s, 3H), 3.48 (s,2H); MS (ESI⁺) m/z 520.14 (M+H)⁺.

Example 16

N¹-(4-(2-Aminopyrimidin-4-yloxy)-3-fluorophenyl)-N³-(4-fluorophenyl)malonamide

A mixture ofN¹-(4-(2-(4-methoxybenzylamino)pyrimidin-4-yloxy)-3-fluorophenyl)-N³-(4-fluorophenyl)malonamide(Example 14, 25 mg, 0.048 mmol), anisole (52 mg, 0.48 mmol) in TFA (1mL) was heated at 85° C. for 6 h. The TFA was removed under vacuum andthe residue partitioned between EtOAc and saturated aq. NaHCO₃ solution.The EtOAc phase was washed with brine, dried (MgSO₄), and concentratedin vacuo. Flash chromatography on SiO₂ using EtOAc then 1-2% MeOH inCH₂Cl₂ as eluents gave the title compound (12 mg, 63%) as an off-whitesolid. ¹H NMR (DMSO-d₆) δ 11.00 (s, 1H), 10.51 (s, 1H), 8.02 (s, 1H),7.66 (dd, 1H, J=12.6, 2.0 Hz), 7.42-7.31 (m, 2H), 7.32-7.27 (m, 1H),7.23 (t, 2H, J=8.6 Hz), 7.16 (t, 2H, J=9.1 Hz), 6.91 (s, 2H), 3.73 (s,2H); MS (ESI⁺) m/z 400.11 (M+H)⁺.

Example 17

1-(4-(2-Aminopyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea

The title compound was prepared from1-(4-(2-(4-methoxybenzylamino)pyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea(Example 15, 20 mg, 0.039 mmol) using a similar procedure described forExample 16. Flash chromatography on SiO₂ using EtOAc then 1-2% MeOH inCH₂Cl₂ as eluents gave the title compound (10 mg, 62%) as an off-whitesolid. ¹H NMR (DMSO-d₆) δ 11.01 (s, 1H), 10.52 (s, 1H), 8.20 (d, 1H,J=6.0 Hz), 7.70 (dd, 1H, J=12.1, 2.0 Hz), 7.36-7.30 (m, 6H), 7.16 (dd,2H, J=8.8, 8.8 Hz), 6.45 (d, 1H, J=6.1 Hz), 3.73 (s, 2H); MS (ESI⁺) m/z400.09 (M+H)⁺.

Example 18

N¹-(3-Fluoro-4-(2-(2-morpholinoethylamino)pyridin-4-yloxy)phenyl)-N³-(4-fluorophenyl)malonamide,hydrochloride salt

A) N-(4-(2-Chloropyridin-4-yloxy)-3-fluorophenyl)acetamide

A mixture of N-(3-fluoro-4-hydroxyphenyl)acetamide (Compound A ofExample 13, 1.33 g, 7.87 mmol), 2-chloro-4-nitropyridine (Aldrich, 1.24g, 7.87 mmol), K₂CO₃ (1.6 g, 11.8 mmol), and DMF (25 mL) was heated at100° C. for 9 h. The reaction mixture was concentrated in vacuo and theresidue partitioned between EtOAc and saturated NaHCO₃ solution. TheEtOAc phase was washed with brine, dried (MgSO₄), and concentrated.Flash chromatography using 30-80% EtOAc in hexanes as the eluent gavethe title compound (1.6 g, 73%) as a pale yellow solid. ¹H NMR (DMSO-d₆)δ 10.24 (s, 1H), 8.65 (s, 1H), 7.89-7.64 (m, 1H), 7.56 (s, 1H),7.46-7.19 (m, 2H), 2.06 (s, 3H); MS (ESI⁺) m/z 281.16 (M+H)⁺.

B) N-(4-(2-Chloropyridin-4-yloxy-1-oxide)-3-fluorophenyl)acetamide

A mixture of N-(4-(2-chloropyridin-4-yloxy)-3-fluorophenyl)acetamide(0.98 g, 3.5 mmol), m-chloroperoxybenzoic acid (>90%, 1.3 g, 7.6 mmol),and CHCl₃ (50 mL) was stirred at RT for 60 h. The mixture wasconcentrated and the residue triturated with Et₂O (2×100 mL) to give thetitle compound (0.89 g, 87%) as a pale yellow solid. ¹H NMR (DMSO-d₆) δ10.25 (s, 1H), 8.34 (d, 1H, J=7.1 Hz), 7.80 (d, 1H, J=13.2 Hz), 7.49 (d,1H, J=3.3 Hz), 7.33 (d, 2H, J=4.9 Hz), 7.02 (dd, 1H, J=7.1, 3.3 Hz),2.06 (s, 3H); MS (ESI⁻) m/z 295.04 (M−H).

C)N-(3-Fluoro-4-(2-(2-morpholinoethylamino)pyridin-4-yloxy-1-oxide)phenyl)acetamide

A mixture ofN-(4-(2-chloropyridin-4-yloxy-1-oxide)-3-fluorophenyl)acetamide (205 mg,0.62 mmol), 4-(2-aminoethyl)morpholine (Aldrich, 169 mg, 1.30 mmol), andabsolute EtOH was heated at reflux 16 h. The reaction mixture wasconcentrated in vacuo, the residue treated with H₂O (3 mL) and appliedto a 10 g Varian C-18 cartridge. The cartridge was eluted first with H₂Othen with 30% MeOH in H₂O. The fractions which contained the desiredproduct were pooled, concentrated to 5 mL volume, and extracted 3 timeswith EtOAc. The combined extracts were washed with brine, dried (MgSO₄)and concentrated to give the title compound (100 mg, 40%). ¹H NMR(DMSO-d₆) δ 10.22 (s, 1H), 7.84 (d, 1H, J=6.1 Hz), 7.77 (dd, 1H, J=13.2,2.2 Hz), 7.31 (dd, 1H, J=8.8, 2.2 Hz), 7.24 (t, 1H, J=8.8 Hz), 6.41 (m,1H), 6.13 (dd, 1H, J=5.5, 2.2 Hz), 5.81 (d, 1H, J=2.2 Hz), 3.60-3.52 (m,4H), 3.31-3.28 (m, 2H), 2.38 (t, 2H, J=7.1 Hz), 2.34 (m, 4H), 2.06 (s,3H); MS (ESI⁺) m/z 405.22 (M+H)⁺.

D)N-(3-Fluoro-4-(2-(2-morpholinoethylamino)pyridin-4-yloxy)phenyl)acetamide,trifluoroacetic acid salt

A mixture ofN-(3-fluoro-4-(2-(2-morpholinoethylamino)pyridin-4-yloxy-1-oxide)phenyl)acetamide(100 mg, 0.26 mmol), and triphenylphosphine polymer supported (1.4-2.0mmol/g) on polystyrene (500 mg) and DMF (2 mL) was stirred at 135° C.for 15 h. The mixture was filtered to remove the resin and the resinwashed with DMF and EtOAc. The filtrate and washings were combined andconcentrated. The crude product was purified by preparative HPLC(Shimadzu S5 VP-ODS 20×100 mm) to give the title compound (45 mg, 46%)as a white solid. ¹H NMR (DMSO-d₆) δ 10.33 (s, 1H), 8.02 (d, 1H, J=6.6Hz) 7.84 (dd, 1H, J=13.2, 2.0 Hz), 7.39-7.31 (m, 2H), 6.52 (s, 1H), 6.10(s, 1H), 3.83 (br s, 4H), 3.64 (m, 2H), 3.28 (m, 6H), 2.08 (s, 3H); MS(ESI⁺) m/z 375.12 (M+H)⁺.

E) 4-(4-Amino-2-fluorophenoxy)-N-(2-morpholinoethyl)pyridin-2-amine,hydrochloride salt

A mixture ofN-(3-fluoro-4-(2-(2-morpholinoethylamino)pyridin-4-yloxy)phenyl)acetamidetrifluoroacetate (40 mg), MeOH (1 mL), and 6 M HCl (0.2 mL) was heatedat reflux for 3 h. The reaction mixture was concentrated on a rotaryevaporator and the residue lyophilized to give the title compound (30mg, 76%) as a white solid. ¹H NMR (DMSO-d₆) δ 11.12 (br s, 1H), 8.85 (brs, 1H), 7.95 (d, 1H, J=7.2 Hz), 7.08 (dd, 1H, J=8.8, 8.8 Hz), 6.65-6.63(m, 2H), 6.54 (d, 1H, J=8.3 Hz), 6.31 (br s, 1H), 3.85 (m, 6H), 3.33 (m,6H); MS (ESI⁻) m/z 373.14 (M−H).

F)N¹-(3-Fluoro-4-(2-(2-morpholinoethylamino)pyridin-4-yloxy)phenyl)-N³-(4-fluorophenyl)malonamide

The title compound was prepared from a mixture of4-(4-amino-2-fluorophenoxy)-N-(2-morpholinoethyl)pyridin-2-amine,hydrochloride salt (15 mg, 0.043 mmol),3-(4-fluorophenylamino)-3-oxopropanoic acid (Compound B of Example 1, 10mg, 0.052 mmol), TBTU (17 mg, 0.052 mmol), DIPEA (30 μL), and DMF (1 mL)using a similar procedure described for the preparation of Compound C ofExample 1. The crude product was purified by preparative HPLC (ShimadzuS5 VP-ODS 20×100 mm). The product obtained from HPLC purification wastreated with 1 M HCl and lyophilized to give the title compound (10 mg,40%) as a white solid. ¹H NMR (DMSO-d₆) δ 10.37 (s, 1H), 10.05 (s, 1H),9.90 (br s, 1H), 7.90 (d, 1H, J=6.1 Hz), 7.75 (d, 1H, J=13.2 Hz),7.58-7.55 (m, 2H), 7.53-7.50 (m, 1H), 7.40 (d, 1H, J=8.8 Hz), 7.24 (t,1H, J=8.8 Hz), 7.08-7.03 (m, 3H), 6.39 (d, 1H, J=6.1 Hz), 6.11 (s, 1H),3.80-3.81 (m, 4H), 3.67-3.65 (m, 2H), 3.47 (br s, 2H), 3.20 (br s, 4H);MS (ESI⁺) m/z 512.12 (M+H)⁺.

Example 19

N¹-(3-Fluoro-4-(pyridin-4-yloxy)phenyl)-N³-(4-fluorophenyl)malonamide

A) N¹-(3-Fluoro-4-hydroxyphenyl)-N³-(4-fluorophenyl)malonamide

To a solution of 2-fluoro-4-nitrophenol (Avacado, 1.00 g, 6.37 mmol) in4 mL of tetrahydrofuran and 6 mL of methanol at 0° C. was added zincdust (2.08 g, 31.8 mmol, <10 micron) followed by ammonium chloride (1.70g, 31.8 mmol). The mixture was stirred at room temperature overnight.The heterogeneous mixture was filtered through a thin pad of Celite®with methanol and the filtrate was concentrated in vacuo to give4-amino-2-fluorophenol as a brown solid which was used without furtherpurification (656 mg, 81%).

3-(4-Fluorophenylamino)-3-oxopropanoic acid (Compound B of Example 1,197 mg, 1.00 mmol) was dissolved in dimethylformamide (4 mL).Triethylamine (140 μL, 1.00 mmol) was added and the solution was cooledto 0° C. 4-Amino-2-fluorophenol (Step A of Example 19, 127 mg, 1.00mmol) was added followed bybenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(BOP reagent, 442 mg, 1.00 mmol). The reaction was allowed to warm toroom temperature and was then stirred at room temperature for 3 h. Thereaction mixture was concentrated to remove methylene chloride and waterwas added to precipitate the product. Filtration and trituration withwater gave the title compound (211 mg, 69%) as a white solid. ¹H NMR(CD₃OD) δ 7.61-7.57 (m, 2H), 7.51 (dd, 1H, J=13, 2.5 Hz), 7.08-6.99 (m,3H), 6.88 (t, 1H, J=9.4 Hz), 3.51 (s, 2H); MS (ESI⁺) m/z 307.44 (M+H)⁺.

B) N¹-(3-Fluoro-4-(pyridin-4-yloxy)phenyl)-N³-(4-fluorophenyl)malonamide

N¹-(3-Fluoro-4-hydroxyphenyl)-N³-(4-fluorophenyl)malonamide (31 mg, 0.10mmol), copper(II) acetate (27 mg, 0.15 mmol), pyridin-4-ylboronic acid(25 mg, 0.20 mmol), and pyridine (16 μL, 0.20 mmol) were placed in apressure tube in that order. The tube was charged with methylenechloride (0.5 mL) and sealed. The reaction was stirred at 120° C. for 5h. The reaction mixture was filtered through silica gel using 5%methanol/ethyl acetate. After concentration, the crude product waspurified by prep HPLC. The appropriate fraction was concentrated toremove methanol and the resulting aqueous solution was made basic withsaturated NaHCO₃ solution (5 mL). The aqueous solution was extractedwith EtOAc (3×10 mL) and the combined organic extracts were dried overanhydrous Na₂SO₄ and concentrated in vacuo. The product was treated with4N HCl in dioxane and concentrated. Lyophilization with water gave thetitle compound (8 mg, 21%) as a yellow solid. ¹H NMR (CD₃OD) δ 8.31 (d,2H, J=6.1 Hz), 7.72 (dd, 1H, J=12.7, 2.4 Hz), 7.49-7.46 (m, 2H),7.27-7.25 (m, 1H), 7.15 (t, 1H, J=8.8 Hz), 6.97 (t, 2H, J=8.7 Hz), 6.85(dd, 2H, J=5.1, 1.2 Hz), 3.46 (s, 2H); MS (ESI⁺) m/z 384.21 (M+H)⁺.

Example 20

N¹-(4-(2-Chloropyridin-4-yloxy)-3-fluorophenyl)-N³-(4-fluorophenyl)malonamide

A) 2-Fluoro-4-aminophenol

A mixture of platinum oxide (0.010 g) and 2-fluoro-4-nitrophenol(Aldrich, 1.24 g, 7.78 mmol, 1.0 eq) in MeOH (100 ml) were stirred undera H₂ atmosphere at 50 psi at room temperature. The reaction mixture wasfiltered through celite and the filtrate concentrated in vacuo to affordthe title compound (1.00 g, 100%), as a solid which was used withoutfurther purification. ¹H NMR (DMSO-d₆) δ 8.57 (s, 1H), 6.46-6.47 (m,1H), 6.33-6.46 (m, 1H), 6.19-6.21 (m, 1H), 4.79 (s, 2H); MS (ESI⁺) m/z128 (M+H)⁺.

B) 4-(2-Chloropyridin-4-yloxy)-3-fluorobenzenamine

Sodium hydride (60%, 0.104 g, 2.60 mmol, 1.1 eq) was added to a solutionof 2-fluoro-4-aminophenol (0.30 g, 2.36 mmol, 1.0 eq) in DMF (6.5 mL) atroom temperature and the reaction mixture was stirred for 30 minutes.2-Chloro-4-nitropyridine (Aldrich, 0.374 g, 2.36 mmol, 1.0 eq) was addedand the reaction mixture was heated to 90° C. for 12 h. The reactionmixture was cooled to room temperature, quenched with saturated aqueousNaCl solution and extracted with ethyl acetate (3×70 mL). The combinedorganic extracts were washed with 10% aq. LiCl solution (3×70 mL), driedover Na₂SO₄, filtered and the filtrate concentrated in vacuo to affordthe title compound (0.430 g, 76%) which was used without furtherpurification. ¹H NMR (DMSO-d₆) δ 8.27 (d, 1H, J=5.7 Hz), 6.90-7.04 (m,3H), 6.42-6.54 (m, 2H), 5.54 (s, 2H); MS (ESI⁺) m/z 239 (M+H)⁺; HRMS(ESI⁺) calcd.: 239.0387. found: 239.0391.

C)N¹-(4-(2-Chloropyridin-4-yloxy)-3-fluorophenyl)-N³-(4-fluorophenylmalonamide

Diisopropylethylamine (0.091 mL, 0.525 mmol, 2.5 eq) was added to asolution of 4-(2-chloropyridin-4-yloxy)-3-fluorobenzenamine (0.050 g,0.21 mmol, 1.0 eq), 3-(4-fluorophenylamino)-3-oxopropanoic acid(Compound B of Example 1, 0.041 g, 0.21 mmol, 1.0 eq), and PyBroP (0.117g, 0.252 mmol, 1.2 eq) in CH₂Cl₂ (1.0 mL) at 0° C. The reaction mixturewas warmed to room temperature and stirred for 12 h. The reactionmixture was quenched with saturated aqueous NaCl solution, and themixture was extracted with CH₂Cl₂ (3×20 mL). The combined organicextracts were dried over Na₂SO₄, filtered and the filtrate concentratedin vacuo. The residue was purified by silica gel flash chromatography(Merck, 40-63 μM, 230-240 mesh, eluting 3/1 ethyl acetate/hexane) toafford the title compound (0.056 g, 64%) as a solid. ¹H NMR (DMSO-d₆) δ10.61 (s, 1H), 10.34 (s, 1H), 8.36-8.38 (m, 1H), 7.91-7.93 (m, 1H),7.67-7.71 (m, 2H), 7.46-7.48 (m, 2H), 7.04-7.26 (m, 4H), 3.56 (s, 2H);MS (ESI⁺) m/z 418 (M+H)⁺; HRMS (ESI⁺) calcd.: 418.0770. found: 418.0767.

Example 21

1-(4-(2-Chloropyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)thiourea

4-Fluorophenylacetylchloride (Aldrich, 0.072 mL, 0.525 mmol, 2.5 eq) wasadded to a solution of sodium thiocyanate (0.056 g, 0.695 mmol, 3.3 eq)in ethyl acetate (2.0 mL) at room temperature and the reaction mixturewas stirred for 1.5 h to afford a solution of 2-(4-fluorophenyl)ethanoylisothiocyanate (0.263 M). A solution of4-(2-chloropyridin-4-yloxy)-3-fluorobenzenamine (0.050 g, 0.21 mmol, 1.0eq) in CH₂Cl₂ (1.0 mL) was added dropwise to the2-(4-fluorophenyl)ethanoyl isothiocyanate solution and the reactionmixture was stirred at room temperature for 12 h. The reaction mixturewas concentrated in vacuo and the resulting residue was purified bysilica gel flash chromatography (Merck, 40-63 μM, 230-240 mesh, eluting3/1 hexane/ethyl acetate) to afford the title compound (0.058 g, 64%) asa solid. ¹H NMR (DMSO-d₆) δ 12.46 (s, 1H), 11.84 (s, 1H), 8.35-8.33 (m,1H), 8.02-8.33 (m, 1H), 6.99-7.52 (m, 8H), 3.84 (s, 2H); MS (ESI⁺) m/z434 (M+H)⁺; HRMS (ESI⁺) calcd.: 434.0542. found: 434.0547.

Example 22

N¹-(4-(2-(Benzylamino)pyridin-4-yloxy)-3-fluorophenyl)-N³-(4-fluorophenyl)malonamide

A) tert-Butyl 4-(2-chloropyridin-4-yloxy)-3-fluorophenylcarbamate

Di-tert-butyl dicarbonate (0.920 g, 4.22 mmol, 4.5 eq) was added to asolution of 4-(2-chloropyridin-4-yloxy)-3-fluorobenzenamine (Compound Bof Example 20, 0.224 g, 0.939 mmol, 1.0 eq) and triethylamine (0.391 mL,3.00 mmol, 3.0 eq) in THF (10 mL) and the reaction mixture was heated at55° C. for 14 h. The reaction mixture was cooled to room temperature andquenched with 1N HCl. The solution was extracted with CH₂Cl₂ (3×70 mL),the combined organic extracts washed with 1N NaOH (100 mL), dried(Na₂SO₄), filtered and concentrated in vacuo. The residue was purifiedby silica gel flash chromatography (Merck, 40-63 μM, 230-240 mesh,eluting 4:1 hexane/ethyl acetate) to afford the title compound (0.270 g,85%). ¹H NMR (DMSO-d₆) δ 8.35-8.36 (m, 1H), 7.55-7.57 (m, 1H), 7.45-7.46(m, 1H), 7.21-7.24 (m, 1H), 6.96-6.97 (m, 2H), 1.40 (s, 9H); MS (ESI⁺)m/z 339 (M+H)⁺; HRMS (ESI⁺) calcd.: 339.0912. found: 339.0915.

B) tert-Butyl-4-(2-(benzylamino)pyridin-4-yloxy)-3-fluorophenylcarbamate

tert-Butyl 4-(2-chloropyridin-4-yloxy)-3-fluorophenylcarbamate (0.100 g,0.295 mmol, 1.0 eq) was added to a degassed solution of dppf.PdCl₂(Matrix Scientific, 0.011 g, 0.0148 mmol, 0.05 eq), dppf (0.012 g, 0.022mmol, 0.075 eq), and NaOt-Bu (0.040 g, 0.414 mmol, 1.4 eq) in toluene atroom temperature. Benzylamine (0.045 mL, 0.414 mmol, 1.4 eq) was addedto the reaction mixture and the resulting solution was stirred at 80° C.for 4 h. The reaction mixture was cooled to room temperature, quenchedwith 1N HCl and the solution extracted with CHCl₃ (3×50 mL). Thecombined organic extracts were washed with 1 N NaOH (70 mL), dried(Na₂SO₄), filtered and concentrated in vacuo. The residue was purifiedby silica gel flash chromatography (Merck, 40-63 μM, 230-240 mesh,eluting 2:1 hexane/ethyl acetate) to afford the title compound (0.020 g,17%). ¹H NMR (CDCl₃) δ 7.80-7.90 (m, 1H), 7.35-7.45 (m, 1H), 7.19-7.24(m, 3H), 6.91-6.93 (m, 2H), 6.59 (br m, 1H), 6.10-6.20 (m, 1H), 5.75 (brm, 1H), 5.30-5.40 (m, 1H), 4.34 (s, 2H), 1.46 (s, 9H); MS (ESI⁺) m/z 410(M+H)⁺; HRMS (ESI⁺) calcd.: 410.1880. found: 410.1884.

C) 4-(4-Amino-2-fluorophenoxy)-N-benzylpyridin-2-amine, hydrochloridesalt

Anhydrous HCl in dioxane (4N, 2.00 mL, 8.00 mmol, 165 eq) was added totert-butyl 4-(2-(benzylamino)pyridin-4-yloxy)-3-fluorophenylcarbamate(0.020 g, 0.0489 mmol, 1.0 eq) and the reaction mixture was stirred atroom temperature for 12 h. The reaction mixture was concentrated invacuo to afford the title compound (0.017 g, 100%) a solid that was usedwithout further purification. MS (ESI⁺) m/z 310 (M+H)⁺; HRMS (ESI⁺)calcd.: 310.1356. found: 310.1364.

D)N¹-(4-(2-(Benzylamino)pyridin-4-yloxy)-3-fluorophenyl)-N³-(4-fluorophenyl)malonamide

Diisopropylethylamine (0.014 mL, 0.081 mmol, 3.5 eq) was added to asolution of 4-(4-amino-2-fluorophenoxy)-N-benzylpyridin-2-amine,hydrochloride salt (0.008 g, 0.023 mmol, 1.0 eq),3-(4-fluorophenylamino)-3-oxopropanoic acid (Compound B of Example 1,0.005 g, 0.023 mmol, 1.0 eq), and PyBroP (0.013 g, 0.028 mmol, 1.2 eq)in CH₂Cl₂ (1.0 mL) at 0° C. The reaction mixture was warmed to roomtemperature and stirred for 16 h. The reaction mixture was concentratedin vacuo and the residue was purified by reverse phase HPLCchromatography (YMC-ODS-A, C-18, S10, 30×500 mm, eluting 20-90% aqueousMeOH with 0.1% TFA, 30 min. gradient). The appropriate fractions wereconcentrated in vacuo, neutralized with sat. aqueous NaHCO₃ solution andthe mixture extracted with CHCl₃ (3×10 mL). The combined organicextracts were dried (Na₂SO₄), filtered and concentrated in vacuo toafford the title compound (0.0025 g, 45%) as a solid. MS (ESI⁺) m/z 489(M+H)⁺; HRMS (ESI⁺) calcd.: 489.1738. found: 489.1743.

Example 23

1-(3-Fluoro-4-(pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea

A) 3-Fluoro-4-(pyridin-4-yloxy)benzenamine

Potassium hydride (30%, 0.520 g, 3.90 mmol, 3.0 eq) was added to asolution of 2-fluoro-4-aminophenol (Compound A of Example 20, 0.254 g,2.00 mmol, 1.5 eq) in DMF (5.0 mL) at room temperature and the reactionmixture was stirred for 15 minutes. 4-Chloro-pyridine (Aldrich, 0.200 g,1.30 mmol, 1.0 eq) was added and the reaction mixture was heated to 150°C. for 2 h. The reaction mixture was cooled to room temperature,quenched with 1N NaOH and the solution extracted with ethyl acetate(3×50 mL). The combined organic extracts were washed with 1N aqueousNaOH (2×30 mL) followed by 10% aqueous LiCl (3×50 mL). The combinedorganic extracts were dried (Na₂SO₄), filtered and concentrated in vacuoto afford the title compound as a solid. ¹H NMR (DMSO-d₆) δ 8.44-8.46(m, 2H), 6.89-7.03 (m, 1H), 6.87-6.88 (m, 2H), 6.44-6.56 (m, 2H), 5.51(s, 2H); MS (ESI⁺) m/z 205 (M+H)⁺; HRMS (ESI⁺) calcd.: 205.0777. found:205.0775.

B)1-(3-Fluoro-4-(pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea

Silver cyanate (0.912 g, 6.08 mmol, 1.05 eq) was added to a solution of4-fluorophenylacetyl chloride (Aldrich, 0.794 mL, 5.79 mmol, 1.0 eq) intoluene (16 mL) at room temperature shielded from light. The reactionmixture was heated to reflux for 60 minutes and then cooled to roomtemperature. The reaction mixture was filtered (Acrodisc, PTFE 0.2 μM)and the resultant 2-(4-fluorophenyl)acetyl isocyanate solution (0.36 M,0.75 mL, 0.27 mmol, 1.1 eq) was added to a solution of3-fluoro-4-(pyridin-4-yloxy)benzenamine (0.050 g, 0.245 mmol, 1.0 eq) inCH₂Cl₂ (2.0 mL) at room temperature. The reaction mixture was stirred atroom temperature for 1 h, quenched with saturated aqueous NaCl solutionand the mixture was extracted with CH₂Cl₂ (3×30 mL). The combinedorganic extracts were dried (Na₂SO₄), filtered and concentrated invacuo. The residue was purified by silica gel flash chromatography(Merck, 40-63 μM, 230-240 mesh, eluting 0-5% MeOH in CHCl₃) to affordthe title compound (0.043 g, 46%) as a solid. ¹H NMR (DMSO-d₆) δ 11.06(s, 1H), 10.60 (s, 1H), 8.47 (s, 2H), 7.77-7.80 (m, 1H), 6.92-7.48 (m,8H), 3.75 (s, 2H); MS (ESI⁺) m/z 384 (M+H)⁺; HRMS (ESI⁺) calcd.:384.1160. found: 384.1147.

Example 24

1-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea

A) 4-(4-Amino-2-fluorophenoxy)-N-benzylpyridin-2-amine

Benzylamine (9.1 mL, 83.8 mmol, 20 eq) was added to4-(2-chloropyridin-4-yloxy)-3-fluorobenzenamine (Compound B of Example20, 1.0 g, 4.19 mmol, 1.0 eq), copper powder (0.266 g, 4.19 mmol, 1.0eq) and K₂CO₃ (0.578 g, 4.19 mmol, 1.0 eq) in a sealed tube and thereaction mixture was heated to 160° C. for 12 h. The reaction mixturewas cooled to room temperature and quenched with saturated aqueous NaClsolution. The solution was extracted with ethyl acetate (3×100 mL), thecombined organic extracts dried (Na₂SO₄), filtered and concentrated invacuo. The residue was purified by preparative reverse phase HPLC (YMCC-180DS-A S10 50×500 mm, eluting 10-90% aqueous MeOH with 0.1% TFA, 30minute gradient) and the appropriate fractions were concentrated invacuo. The concentrate was neutralized with saturated aqueous NaHCO₃solution and extracted with CH₂Cl₂ (3×100 mL). The combined organicextracts were dried (Na₂SO₄), filtered and concentrated in vacuo toafford the title compound (0.675 g, 52%) as a solid. ¹H NMR (CD₃OD) δ7.78-7.80 (m, 1H), 7.28-7.30 (m, 5H), 6.80-6.90 (m, 1H), 6.52-6.55 (m,2H), 6.18-6.20 (m, 1H), 5.87-5.88 (m, 1H), 4.40 (s, 2H); MS (ESI⁺) m/z310 (M+H)⁺; HRMS (ESI⁺) calcd.: 310.1356. found: 310.1360.

B) 4-(4-Amino-2-fluorophenoxy)pyridin-2-amine

Palladium hydroxide on carbon (10%, 0.050 g) was added to a solution of4-(4-amino-2-fluorophenoxy)-N-benzylpyridin-2-amine (0.245 g, 0.790mmol, 1.0 eq) in 5% HCO₂H-MeOH (10 mL) under a blanket of hydrogen (froma balloon) at room temperature. The reaction mixture was stirred at roomtemperature for 12 h, filtered through Celite® and the filtrateconcentrated in vacuo. The residue was purified by reverse phasepreparative HPLC (YMC ODS-A S10 30×500 mm., 10-90% aqueous MeOH with0.1% TFA, 30 minute gradient) and the appropriate fractions wereconcentrated in vacuo. The concentrate was neutralized with saturatedaqueous NaHCO₃ solution and the mixture was extracted with CHCl₃ (3×35mL). The combined organic extracts were dried (Na₂SO₄), filtered andconcentrated in vacuo to afford the title compound (0.045 g, 26%) as asolid. ¹H NMR (CD₃OD) δ 7.62-7.63 (m, 1H), 6.77-6.82 (m, 1H), 6.38-6.47(m, 2H), 6.09-6.11 (m, 1H), 5.83-5.84 (m, 1H); MS (ESI⁺) m/z 220 (M+H)⁺;HRMS (ESI⁺) calcd.: 220.0886. found: 220.0877.

C)1-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea

2-(4-Fluorophenyl)acetyl isocyanate (Compound D of Example 11, 0.362 M,0.351 mL, 0.127 mmol, 1.3 eq) was added to a solution of4-(4-amino-2-fluorophenoxy)pyridin-2-amine (0.022 g, 0.100 mmol, 1.0 eq)in CH₂Cl₂ (2.0 mL) at room temperature. The reaction mixture was stirredfor 13 h at room temperature and then concentrated in vacuo. The residuewas purified by silica gel flash chromatography (Merck gel 40-63 μM,230-240 mesh, 1:1 ethyl acetate/hexane) to afford the title compound(0.025 g, 64%) as a solid. ¹H NMR (CD₃OD) δ 7.62-7.67 (m, 2H), 7.23-7.29(m, 2H), 7.07-7.12 (m, 2H), 6.95-6.99 (m, 2H), 6.12-6.14 (m, 1H),5.86-5.87 (m, 1H), 3.61 (s, 2H); MS (ESI⁺) m/z 399 (M+H)⁺; HRMS (ESI⁺)calcd.: 399.1269. found: 399.1269.

Alternatively, Example 24 was prepared in the following manner:

A′) 4-Chloropicolinamide

A heterogeneous mixture of 4-chloropicolinic acid (TCI America, 5.4 g,34.2 mmol, 1.0 eq) and thionyl chloride (30 mL) were heated at 80° C.for 2 h. The reaction mixture was cooled to room temperature andconcentrated in vacuo. The residue was treated with an ammonia in MeOHsolution (7N, 45 mL) in an ice bath and the reaction mixture was stirredfor 15 minutes. The ice bath was then removed and the reaction waswarmed to room temperature and then stirred for 3 h. The reactionmixture was concentrated in vacuo and the residue purified byrecrystallization from EtOAc to afford the product (5.14 g, 96%) as asolid. ¹H NMR (DMSO-d₆) δ 8.61-8.63 (m, 1H), 8.21 (m, 1H), 8.03-8.04 (m,1H), 7.76-7.83 (m, 2H); MS (ESI⁺) m/z 157 (M+H)⁺.

B′) 4-(4-Amino-2-fluorophenoxy)picolinamide

A solution of 4-amino-2-fluorophenol (Compound A of Example 20, 0.81 g,6.4 mmol, 1.0 eq) in DMF (6.5 mL) was treated with potassiumtert-butoxide (0.79 g, 7.1 mmol, 1.1 eq) at room temperature and thereaction mixture was stirred for 1 h. 4-Chloropicolinamide (1.0 g, 6.4mmol, 1.0 eq) was added and the reaction mixture was heated to 110° C.for 8 h. The reaction was cooled to room temperature and the reactionmixture quenched with water. The resulting heterogeneous solution wasfiltered and the solid material was washed with water. The solid wastriturated with a small amount of MeOH followed by Et₂O. The solid wasfiltered and dried in vacuo to afford the product (1.3 g, 82%) as asolid. ¹H NMR (DMSO-d₆) δ 8.49-8.50 (m, 1H), 8.12 (br s, 1H), 7.71 (brs, 1H), 7.35-7.36 (m, 1H), 7.14-7.16 (m, 1H), 7.01-7.06 (m, 1H),6.44-6.47 (m, 2H), 5.53 (s, 2H); MS (ESI⁺) m/z 248 (M+H)⁺.

C′)1-(4-(2-Carbamoylpyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea

A solution of 2-(4-fluorophenyl)acetyl isocyanate (Compound D of Example11, 0.29 M in toluene, 54.9 mL, 15.9 mmol, 2.1 eq) was added to4-(4-amino-2-fluorophenoxy)picolinamide (1.86 g, 7.53 mmol, 1.0 eq) in10/3 DCM/DMF (65 mL) at room temperature and the reaction mixture wasstirred for 17 h. The reaction mixture was concentrated in vacuo and theresidue redissolved in CHCl₃. The organic layer was washed withsaturated aqueous NaCl, the organic fraction separated, dried (Na₂SO₄),filtered and concentrated in vacuo. The residue was purified by silicagel chromatography (eluting 1/3 hexane/EtOAc, then to elute product 5%MeOH in CHCl₃), and the appropriate fractions concentrated in vacuo toafford the product (2.2 g, 69%) as a solid. ¹H NMR (DMSO-d₆) δ 11.07 (s,1H), 10.62 (s, 1H), 8.54 (d, 1H, J=5.60 Hz), 8.16-8.19 (m, 1H),7.76-7.84 (m, 2H), 7.35-7.49 (m, 5H), 7.16-7.23 (m, 3H), 3.76 (s, 2H);MS (ESI⁺) m/z 427 (M+H)⁺. HRMS (ESI⁺) calcd.: 427.1218. found: 427.1214.

D′)1-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,hydrochloride salt

Bis-(trifluoroacetoxy)-iodobenzene (Aldrich, 3.09 g, 7.20 mmol, 1.4 eq)was added to a solution of1-(4-(2-carbamoylpyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea(2.19 g, 5.14 mmol, 1.0 eq), water (0.241 mL, 13.4 mmol, 2.6 eq) andpyridine (1.62 mL, 20 mmol, 3.9 eq) in DMF (20 mL) at room temperatureand the reaction mixture was stirred for 5 h. The reaction mixture wasquenched with 1 N HCl and the aqueous solution extracted with Et₂O,discarding the organic layer. The aqueous layer was neutralized with 1 NNaOH and extracted with EtOAc. The combined organic layers were washedwith 10% aq LiCl, dried (Na₂SO₄), filtered and concentrated in vacuo.The residue was purified by silica gel chromatography (eluting with 0-5%MeOH in CHCl₃) and the appropriate fractions were concentrated in vacuo.The residue was dissolved in THF (50 mL) cooled to 0° C. and treatedwith anhydrous HCl (4N, 10 mL, 40 mmol, 7.8 eq). The reaction mixturewas allowed to warm to room temperature and stirred for 2 h resulting ina heterogeneous solution. The solution was filtered and the solid washedwith Et₂O and dried in vacuo to afford the title compound (1.38 g, 63%)as a solid. ¹H NMR (DMSO-d₆)

δ 11.09 (s, 1H), 10.65 (s, 1H), 7.97-8.00 (m, 1H), 7.83-7.90 (m, 3H),7.35-7.48 (m, 4H), 7.15-7.21 (m, 2H), 6.70-6.72 (m, 1H), 6.16-6.17 (m,1H), 3.77 (s, 2H); MS (ESI⁺) m/z 399 (M+H)⁺. HRMS (ESI⁺) calcd.:399.1269; found: 399.1258. Elem analysis for C₂₀H₁₆N₄O₃F₂ 1.0 HCl . . .0.22H₂O

Calcd.: C, 54.75; H, 4.01; N, 12.77, Cl; 8.08. Found: C, 54.75; H, 4.35;N, 4.35, Cl; 8.06.

Example 25

N-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-2-fluoro-5-methylbenzamide

Diisopropylethylamine (0.035 mL, 0.200 mmol, 2.0 eq) was added to asolution of 4-(4-amino-2-fluorophenoxy)pyridin-2-amine (Compound B ofExample 24, 0.022 g, 0.100 mmol, 1.0 eq), 2-fluoro-5-methyl benzoic acid(Aldrich, 0.015 g, 0.100 mmol, 1.0 eq), EDCI (0.021 g, 0.11 mmol, 1.1eq) and HOBT (0.014 g, 0.100 mmol, 1.0 eq) in DMF (0.700 mL) at roomtemperature. The reaction mixture was stirred at room temperature for 8h, quenched with saturated aqueous NaHCO₃ solution and extracted withCHCl₃ (3×10 mL). The combined organic extracts were dried (Na₂SO₄),filtered and concentrated in vacuo. The residue was purified by reversephase preparative HPLC (YMC ODS-A S10 30×500 mm, 30-90% aqueous MeOHwith 0.1% TFA, 30 minute gradient) and the appropriate fractions wereconcentrated in vacuo. The concentrate was neutralized with saturatedaqueous NaHCO₃ solution and the mixture extracted with CHCl₃ (3×30 mL).The combined organics were dried (Na₂SO₄), filtered and concentrated invacuo to afford the title compound (0.014 g, 40%) as a solid. ¹H NMR(CD₃OD) δ 7.67-7.80 (m, 2H), 7.36-7.45 (m, 3H), 7.03-7.14 (m, 2H),6.14-6.16 (m, 1H), 5.89-5.90 (m, 1H), 2.29 (s, 3H); MS (ESI⁺) m/z 356(M+H)⁺; HRMS (ESI⁺) calcd.: 356.1211. found: 356.1203.

Example 26

N¹-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-N³-(4-fluorophenylmalonamide

Diisopropylethylamine (0.105 mL, 0.604 mmol, 3.3 eq) was added to asolution of 4-(4-amino-2-fluorophenoxy)pyridin-2-amine (Compound B ofExample 24, 0.040 g, 0.183 mmol, 1.0 eq),3-(4-fluorophenylamino)-3-oxopropanoic acid (Compound B of Example 1,0.054 g, 0.274 mmol, 1.5 eq), and PyBroP (0.139 g, 0.298 mmol, 1.6 eq)in CH₂Cl₂ (2.0 mL) at 0° C. The reaction mixture was warmed to roomtemperature and stirred for 18 h. The reaction mixture was quenched withsaturated aqueous NaHCO₃ and the solution extracted with CHCl₃ (3×10mL). The combined organic extracts were dried (Na₂SO₄), filtered andconcentrated in vacuo. The residue was purified by silica gel flashchromatography (Merck 40-63 μM, 230-240 mesh, eluting 0-6% MeOH in CHCl₃to afford the title compound (0.056 g, 77%) as a solid. ¹H NMR (CD₃OD) δ7.67-7.68 (m, 2H), 7.48-7.52 (m, 2H), 7.13-7.25 (m, 1H), 7.10-7.12 (m,1H), 6.94-6.99 (m, 2H), 6.16-6.17 (m, 1H), 5.88-5.89 (m, 1H), 3.30 (s,2H); MS (ESI) m/z 399 (M−H⁺); HRMS (ESI⁺) calcd.: 399.1269. found:399.1261.

Example 27

1-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)thiourea

4-Fluorophenylacetylchloride (Aldrich, 0.017 mL, 0.126 mmol, 2.5 eq) wasadded to a solution of sodium thiocyanate (0.014 g, 0.176 mmol, 3.5 eq)in ethyl acetate (1.0 mL) at room temperature and the reaction mixturewas stirred for 1.5 h to afford a 2-(4-fluorophenyl)ethanoylisothiocyanate solution (0.126 M).4-(4-Amino-2-fluorophenoxy)pyridin-2-amine (Compound B of Example 24,0.011 g, 0.050 mmol, 1.0 eq) was dissolved in CH₂Cl₂ (1.0 mL) and2-(4-fluorophenyl)ethanoyl isothiocyanate (0.126 M, 0.50 mL, 0.063 mmol,1.3 eq) was added and the reaction mixture was stirred at roomtemperature for 20 h. The reaction mixture was concentrated in vacuo andthe resulting residue was purified by silica gel flash chromatography(Merck, 40-63 μM, 230-240 mesh, eluting 0-6% MeOH in CHCl₃) to affordthe title compound (0.008 g, 38%) as a solid. ¹H NMR (CD₃OD) δ 7.85-7.95(m, 1H), 7.67-7.69 (m, 1H), 7.13-7.28 (m, 4H), 6.95-7.00 (m, 2H),6.05-6.15 (m, 1H), 5.90-5.91 (m, 1H), 3.65 (s, 2H); MS (ESI⁺) m/z 415(M+H)⁺; HRMS (ESI⁺) calculated: 415.1040. found: 415.1041.

Example 28

1-(3-Fluoro-4-(2-(4-fluorophenylamino)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea

A)N-(3-Fluoro-4-(2-(4-fluorophenylamino)pyridin-4-yloxy-1-oxide)phenyl)acetamide

A mixtureN-(4-(2-chloropyridin-4-yloxy-1-oxide)-3-fluorophenyl)acetamide(Compound B of Example 18, 62 mg, 0.21 mmol), 4-fluoroaniline (47 mg,0.42 mmol), and 2-methoxyethyl ether (91 mL) was heated at 140° C. for15 min. The mixture was cooled to RT, diluted with EtOAc (20 mL), washedwith saturated NaHCO₃ solution and brine (several times), dried (MgSO₄),and concentrated in vacuo to give a 4:1 mixture of the title compoundand the parent pyridine as a light brown oil (45 mg, 58%). The productwas used in the subsequent step without any further purification. MS(ESI⁺) m/z 372.1 (M+H)⁺.

B)N-(3-Fluoro-4-(2-(4-fluorophenylamino)pyridin-4-yloxy)phenyl)acetamide

A mixture ofN-(3-fluoro-4-(2-(4-fluorophenylamino)pyridin-4-yloxy-1-oxide)phenyl)acetamide(45 mg), triphenylphosphine polymer supported (˜3 mmol/g) on polystyrene(200 mg, Fluka) and DMF (3 mL) was heated at 135° C. for 48 h. The resinwas filtered off, washed with DMF and EtOAc. The filtrate and washingswere combined and concentrated in vacuo. The crude product was purifiedby flash chromatography using 30-80% EtOAc in hexanes as the eluent togive the title compound (22 mg, 51%) as a pink solid. ¹H NMR (DMSO-d₆) δ10.24 (s, 1H), 8.99 (s, 1H), 8.03 (d, 1H, J=6.3 Hz), 7.80 (dd, 1H,J=13.0, 2.1 Hz), 7.63-7.60 (m, 2H), 7.36-7.29 (m, 2H), 7.05 (dd, 1H,J=9.1, 8.6 Hz), 6.44 (dd, 1H, J=5.5, 2.2 Hz), 6.09 (d, 1H, J=2 Hz), 2.07(s, 3H); MS (ESI⁺) m/z 356.7 (M+H)⁺.

C) 4-(4-Amino-2-fluorophenoxy)-N-(4-fluorophenyl)pyridin-2-amine

A mixture ofN-(3-fluoro-4-(2-(4-fluorophenylamino)pyridin-4-yloxy)phenyl)acetamide(18 mg, 0.051 mmol), 6 M HCl (0.1 mL, 0.60 mmol) and MeOH (1.5 mL) washeated at reflux for 2 h. The mixture was concentrated in vacuo and theresidue made basic with saturated aq. NaHCO₃ solution then extractedwith EtOAc. The extract was dried (MgSO₄) and concentrated in vacuo togive the title compound (14 mg, 88%) as a red gum. ¹H NMR (DMSO-d₆) δ8.97 (s, 1H), 7.98 (d, 1H, J=5.8 Hz), 7.64-7.60 (m, 2H), 7.05 (dd, 2H,J=9.1, 8.8 Hz), 6.97 (dd, 1H, J=9.4, 8.8 Hz), 6.51 (dd, 1H, J=13.3, 2.6Hz), 6.40 (ddd, 2H, J=9.0, 6.2, 2.1 Hz), 6.08 (d, 1H, J=2.0 Hz), 5.44(br s, 2H); MS (ESI⁺) m/z 314.17 (M+H)⁺.

D)1-(3-Fluoro-4-(2-(4-fluorophenylamino)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea

A solution 4-(4-amino-2-fluorophenoxy)-N-(4-fluorophenyl)pyridin-2-amine(11 mg, 0.035 mmol) in THF (1 mL) was cooled in an ice bath and treatedwith a solution of 2-(4-fluorophenyl)acetyl isocyanate in toluene(Compound D of Example 11, 250 μL, 0.070 mmol) and stirred at RT for 2h. The mixture was concentrated in vacuo and the residue triturated withisopropyl ether to give the title compound (11 mg, 65%) as a whitesolid. ¹H NMR (DMSO-d₆) δ 11.04 (s, 1H), 10.56 (s, 1H), 9.01 (s, 1H),8.03 (d, 1H, J=5.6 Hz), 7.77 (dd, 1H, J=13.3, 2.0 Hz), 7.63-7.60 (m,2H), 7.41-7.31 (m, 5H), 7.19-7.14 (m, 2H), 7.05 (dd, 1H, J=9.1, 8.5 Hz),6.43 (dd, 1H, J=6.2, 2.1 Hz), 6.10 (d, 1H, J=2.1 Hz), 3.74 (s, 2H); MS(ESI⁺) m/z 493.2 (M+H)⁺.

Example 29

N¹-(4-(6-(4-(Benzyloxy)phenylamino)pyrimidin-4-yloxy)-3-fluorophenyl)-N³-(4-fluorophenyl)malonamide

A)N-(4-(6-(4-(Benzyloxy)phenylamino)pyrimidin-4-yloxy)-3-fluorophenyl)acetamide

A mixture of N-(4-(6-chloropyrimidin-4-yloxy)-3-fluorophenyl)acetamide(Compound B of Example 13, 281 mg, 1.00 mmol), 4-benzyloxyaniline(Aldrich, 398 mg, 2.00 mmol), and 2-methoxyethyl ether (2 mL) was heatedat 160° C. for 45 min. The cooled mixture was treated with H₂O (50 mL)and extracted with EtOAc (100 mL). The EtOAc extract was washed withbrine (3×25 mL), dried (MgSO₄) and concentrated in vacuo to give thetitle compound (200 mg, 22%) as a purple solid. ¹H NMR (400 MHz,DMSO-d₆) δ 10.19 (s, 1H), 9.43 (s, 1H), 8.23 (s, 1H), 7.72 (dd, 1H,J=12.5, 2.0 Hz), 7.44-7.42 (m, 4H), 7.38 (dd, 2H, J=8.0, 6.9 Hz),7.33-7.23 (m, 3H), 6.98 (d, 2H, J=9.0 Hz), 6.07 (s, 1H), 5.07 (s, 2H),2.05 (s, 3H); MS (ESI⁺) m/z 445.13 (M+H)⁺.

B) 6-(4-Amino-2-fluorophenoxy)-N-(4-(benzyloxy)phenyl)pyrimidin-4-amine

A mixture ofN-(4-(6-(4-(benzyloxy)phenylamino)pyrimidin-4-yloxy)-3-fluorophenyl)acetamide(150 mg, 0.34 mmol), 6 M HCl (0.5 mL) and MeOH (3 mL) was heated atreflux for 2 h. The mixture was concentrated to remove the MeOH and theresidue treated with saturated NaHCO₃ solution and extracted with EtOAc.The organic phase was dried (MgSO₄) and concentrated in vacuo to givethe title compound (123 mg, 90%) as a pink solid. ¹H NMR (DMSO-d₆): δ9.37 (s, 1H), 8.24 (s, 1H), 7.46-7.31 (m, 7H), 6.99-6.92 (m, 3H), 6.48(dd, 1H, J=12.5, 2.7 Hz), 6.39 (dd, 1H, J=8.6, 2.7 Hz), 5.97 (s, 1H),5.39 (br s, 2H), 5.08 (s, 2H); MS (ESI⁺) m/z 403.09 (M+H)⁺.

C)N-(4-(6-(4-(Benzyloxy)phenylamino)pyrimidin-4-yloxy)-3-fluorophenyl)-N³-(4-fluorophenyl)malonamide

The title compound was prepared from a mixture6-(4-amino-2-fluorophenoxy)-N-(4-(benzyloxy)phenyl)pyrimidin-4-amine (45mg, 0.11 mmol), 3-(4-fluorophenylamino)-3-oxopropanoic acid (Compound Bof Example 1, 24 mg, 0.12 mmol), TBTU (48 mg, 0.15 mmol), DIPEA (0.26mL, 0.15 mmol), and DMF (1 mL) using a similar procedure described forthe preparation of Compound C of Example 1. The crude product wastriturated with isopropyl ether to give the title compound (56 mg, 88%)as a pink solid. ¹H NMR (DMSO-d₆) δ 10.47 (s, 1H), 10.27 (s, 1H), 9.45(s, 1H), 8.25 (s, 1H), 7.77 (dd, 1H, J=12.7, 2.0 Hz), 7.65-7.62 (m, 2H),7.46 (d, 4H, J=7.3 Hz), 7.40 (dd, 2H, J=7.6, 7.3 Hz), 7.37-7.29 (m, 3H),7.17 (dd, 2H, J=9.0, 8.3 Hz), 7.00 (d, 2H, J=9.0 Hz) 6.09 (s, 1H), 5.09(s, 2H) 3.49 (s, 2H); MS (ESI⁺) m/z 582.3 (M+H)⁺.

Example 30

1-(4-(6-(4-(Benzyloxy)phenylamino)pyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea

The title compound was prepared from6-(4-amino-2-fluorophenoxy)-N-(4-(benzyloxy)phenyl)pyrimidin-4-amine(Compound B of Example 29, 45 mg, 0.11 mmol) and a solution of2-(4-fluorophenyl)acetyl isocyanate in toluene (Compound D of Example11, 0.13 mmol) in THF using a similar procedure described for thepreparation of Compound E of Example 11. The crude product wastriturated with isopropyl ether to give the title compound (58 mg, 90%)as a pink solid. ¹H NMR (DMSO-d₆) δ 11.02 (s, 1H), 10.54 (s, 1H), 9.46(s, 1H), 8.24 (s, 1H), 7.70 (dd, 1H, J=12.7, 2.4 Hz), 7.46-7.26 (m, 9H),7.18 (dd, 2H, J=9.6, 8.3 Hz), 7.00 (d, 2H, J=9.6 Hz), 6.11 (s, 1H), 5.09(s, 2H), 3.75 (s, 2H); MS (ESI⁺) m/z 582.3 (M+H)⁺.

Example 31

1-(3-Fluoro-4-(2-(4-fluorophenylamino)pyrimidin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea

A) N-(4-(2-Chloropyrimidin-4-yloxy)-3-fluorophenyl)acetamide

A mixture of 2,4-dichloropyrimidine (Aldrich, 1.5 g, 10.0 mmol),N-(3-fluoro-4-hydroxyphenyl)acetamide (0.85 g, 5.0 mmol), K₂CO₃ (0.76 g,5.5 mmol), and CH₃CN (100 mL) was heated at reflux for 2 h. The mixturewas concentrated and the residue partitioned between EtOAc and saturatedNaHCO₃ solution. The EtOAc phase was washed with sat NaHCO₃ solution,brine, dried (MgSO₄) and concentrated in vacuo. The crude product waspurified by flash chromatography using a gradient form 30% EtOAc inhexanes to 100% EtOAc to give the title compound (1.1 g, 78%) as a whitesolid. ¹H NMR (DMSO-d₆) δ 10.22 (s, 1H), 8.63 (d, 1H, J=5.6 Hz), 7.74(dd, 1H, J=12.6, 2.4 Hz), 7.34-7.26 (m, 3H), 2.01 (s, 3H).

B)N-(3-Fluoro-4-(2-(4-fluorophenylamino)pyrimidin-4-yloxy)phenyl)acetamide

A mixture of N-(4-(2-chloropyrimidin-4-yloxy)-3-fluorophenyl)acetamide(100 mg, 0.36 mmol), 4-fluoroaniline (Aldrich, 40 mg, 0.36 mmol), and1,4-dioxane (3 mL) was heated at reflux for 2 h. The mixture wasconcentrated in vacuo and the residue triturated with ether to give agray solid. The product was dissolved in MeOH, treated with silica gel(150 mg) and the mixture concentrated to dryness. The compound wasconcentrated down on silica gel and applied to a silica gel column andeluted first with EtOAc then with 100:1 MeOH/NH₄OH in CH₂Cl₂ to give thetitle compound (40 mg, 31%) as a white solid. ¹H NMR (DMSO-d₆) δ 10.19(s, 1H), 9.61 (s, 1H), 8.33 (d, 1H, J=5.6 Hz), 7.71 (d, 1H, J=12.7 Hz),7.40 (s, 2H), 7.30-7.26 (m, 2H), 6.86 (dd, 2H, J=8.3, 8.3 Hz), 6.50 (d,1H, J=5.4 Hz), 2.05 (s, 3H); MS (ESI⁺) m/z 357.13 (M+H)⁺.

C) 4-(4-Amino-2-fluorophenoxy)-N-(4-fluorophenyl)pyrimidin-2-amine

A mixture ofN-(3-fluoro-4-(2-(4-fluorophenylamino)pyrimidin-4-yloxy)phenyl)acetamide(32 mg, 0.09 mmol), 6 M HCl (0.2 mL) and MeOH (2 mL) was heated atreflux for 2 h. The mixture was cooled, diluted with EtOAc (20 mL),washed with saturated NaHCO₃ solution and brine, dried (MgSO₄), andconcentrated in vacuo. Flash chromatography on SiO₂ using 30-40% EtOAcin hexanes containing 1% Et₃N gave the title compound (15 mg, 46%) as awhite solid. ¹H NMR (DMSO-d₆) δ 9.55 (s, 1H), 8.25 (d, 1H, J=5.5 Hz),7.43 (br s, 2H), 6.92-6.85 (m, 3H), 6.45 (dd, 1H, J=13.5, 2.1 Hz),6.38-6.35 (m, 2H), 5.35 (br s, 2H). MS (ESI⁺) m/z 315.17 (M+H)⁺.

D)1-(3-Fluoro-4-(2-(4-fluorophenylamino)pyrimidin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea

A solution of4-(4-amino-2-fluorophenoxy)-N-(4-fluorophenyl)pyrimidin-2-amine (10 mg,0.032 mmol) in THF (1 mL) was cooled in an ice bath and treated with asolution of 2-(4-fluorophenyl)acetyl isocyanate in toluene (Compound Dof Example of 11, 228 μL, 0.064 mmol) and stirred at RT for 2 h. Thereaction mixture was concentrated in vacuo and the residue trituratedwith isopropyl ether to give the title compound (15 mg, 93%) as a whitesolid. ¹H NMR (DMSO-d₆) δ 11.06 (s, 1H), 10.56 (s, 1H), 9.68 (s, 1H),8.39 (d, 1H, J=5.7 Hz), 7.76 (dd, 1H, J=13.5, 2.1 Hz), 7.43 (br s, 2H),7.46-7.35 (m, 6H), 7.18 (dd, 2H, J=8.8, 8.8 Hz), 6.57 (d, 1H, J=5.4 Hz),3.76 (s, 2H); MS (ESI⁺) m/z 492.0 (M+H)⁺.

Example 32

1-(2-(4-Fluorophenyl)acetyl)-3-(4-((2-(pyridin-2-ylamino)thiazol-5-yl)methylamino)phenyl)thiourea

A) N¹-((2-(Pyridin-2-ylamino)thiazol-5-yl)methyl)benzene-1,4-diamine

A solution of 2-(pyridine-2-ylamino)-thiazole-5-carbaldehyde (0.10 g,0.49 mmol, WO2004/001059), benzene-1,4-diamine (0.105 g, 0.97 mmol) andtriethylsilane (0.19 mL, 1.2 mmol) in CH₂Cl₂-TFA (3:1, 4 mL) was stirredat ambient temperature for 4 h. The reaction mixture was concentrated invacuo and the residue partitioned between CH₂Cl₂ and saturated aqueousNaHCO₃ solution. The organic phase was washed with saturated aqueousNaHCO₃ solution, brine, dried (MgSO₄) and concentrated in vacuo. Thecrude product which contained the title compound along with the startingaldehyde and benzene-1,4-diamine was carried on directly into the nextstep.

B)1-(2-(4-Fluorophenyl)acetyl)-3-(4-((2-(pyridin-2-ylamino)thiazol-5-yl)methylamino)phenyl)thiourea

4-Fluorophenylacetyl chloride (7.4 μL, 0.053 mmol) was added to asuspension of NaSCN (4.5 mg, 0.055 mmol) in EtOAc (0.5 mL) and theresulting mixture was stirred at RT for 30 min. This mixture was thenadded to a solution of the above mixture obtained in A (14.5 mg) inCH₂Cl₂ (0.5 ml) and the resulting mixture was stirred at ambienttemperature for 2 h. The reaction mixture was concentrated in vacuo andthe residue was purified by flash chromatography on SiO₂ using a 2-5%MeOH—CHCl₃ gradient elution to give the title compound (2 mg) as anorange film. MS (ESI⁺) m/z 493.2 (M+H)⁺.

Example 33

1-(4-(3-Ethylpyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,hydrochloride salt

A) 4-(2-Fluoro-4-nitrophenoxy)-3-iodopyridine

A mixture of 4-chloro-3-iodopyridine (1.50 g, 6.30 mmol, preparedaccording to Tabanella, S. et al. Org. Biomol. Chem. 2003, 1,4254-4261.), 2-fluoro-nitrophenol (Lancaster, 2.0 g, 12.7 mmol), DIPEA(5 mL), and NMP (10 mL) was heated at 150° C. After 12 h, more2-fluoro-nitrophenol (0.50 g, 3.18 mmol) was added to the reactionmixture and heating was continued for 4 h. Most of the volatilecomponents were removed under vacuum at 75° C., the residue treated withsaturated aq. NaHCO₃ solution (150 mL) and extracted with EtOAc (2×100mL). The combined extracts were washed with brine, dried (MgSO₄) andconcentrated in vacuo to give the crude product. Purification by flashchromatography on silica gel, using 0-100% CH₂Cl₂/hexanes then 2%MeOH/CH₂Cl₂ gave the title compound (1.0 g, 43%) as a yellow solid. ¹HNMR (DMSO-d₆) δ 8.96 (s, 1H), 8.47 (d, 2H, J=5.5 Hz), 8.44 (dd, 1H,J=2.7, 9.2 Hz), 7.49 (dd, 1H, J=8.8, 8.2 Hz), 7.07 (d, 1H, J=5.5 Hz); MS(ESI⁺): m/z 361.05 (M+H)⁺.

B) 4-(2-Fluoro-4-nitrophenoxy)-3-vinylpyridine

A solution of 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridine (200 mg, 0.56mmol), tributylvinyltin (212 mg, 0.67 mmol) in DMF (1 mL) was treatedwith CsF (169 mg, 1.12 mmol) followed by (Ph₃P)₄Pd (36 mg, 0.031 mmol)and CuI (10 mg, 0.056 mmol) and the mixture was heated at 45° C. for 1h. The mixture was cooled, diluted with CH₂Cl₂ (15 mL) and H₂O (10 mL),shaken vigorously and then filtered through Celite®. The filter cake waswashed with 1:1 CH₂Cl₂/EtOAc and the washings were combined with thefiltrate. The solution was washed with brine, dried (MgSO₄) andconcentrated in vacuo to give a brown oil. The crude product waspurified by flash chromatography on SiO₂ using 0-2% MeOH/CH₂Cl₂ to givea semi-pure product. The product was treated with 2 M HCl/Et₂O (10 mL)and the precipitated hydrochloride derivative collected by filtrationand washed with Et₂O and EtOAc to a yellow solid (145 mg, 87%). ¹H NMR(DMSO-d₆) δ 9.11 (s, 1H), 8.64 (s, 1H), 8.51-8.48 (m, 1H), 8.24 (d, 1H,J=7.7 Hz), 7.83-7.79 (m, 1H), 7.28 (d, 1H, J=6.0 Hz), 7.02-6.95 (m, 1H),6.24 (d, 1H, J=17.6 Hz), 5.68 (d, 1H, 11.5 Hz); MS (ESI⁺): m/z 261.18(M+H)⁺.

The above hydrochloride salt was converted to the free-base as follows:The pyridine hydrochloride (230 mg) was stirred with NaHCO₃ (25 mL) andEtOAc (20 mL) until homogeneous and the EtOAc phase separated, washedwith brine, dried (MgSO₄) and concentrated. The title compound (190 mg)was obtained as a yellow oil.

C) 4-(3-Ethylpyridin-4-yloxy)-3-fluorobenzenamine

A solution of 4-(2-fluoro-4-nitrophenoxy)-3-vinylpyridine (80 mg, 0.30mmol) in 1:1 EtOAc/MeOH (2 mL) was hydrogenated over 10%palladium-carbon (30 mg) for 1 h using H₂ from a latex balloon. Pt₂O (10mg) was added to the mixture and the reaction continued for 1 h. Themixture was filtered through Celite® and concentrated in vacuo to givethe title compound (50 mg, 63%) as a yellow oil. ¹H NMR (DMSO-d₆) δ 8.33(s, 1H), 8.22 (d, 1H, J=5.6 Hz), 6.96 (dd, 1H, J=8.7, 9.1 Hz), 6.50 (dd,1H, J=2.0, 13.7 Hz), 6.56 (d, 1H, J=5.6 Hz), 6.41 (dd, 1H, J=2.5, 6.1Hz), 2.69 (q, 2H, J=7.6 Hz), 1.21 (t, 3H, J=7.6 Hz).

D)1-(4-(3-Ethylpyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,hydrochloride salt

A solution of 4-(3-ethylpyridin-4-yloxy)-3-fluorobenzenamine (23 mg,0.10 mmol) in CH₂Cl₂ (1 mL) was treated with a solution of 0.3 Msolution of 2-(4-fluorophenyl)acetyl isocyanate in toluene (Compound Dof Example 11, 0.33 mL, 0.11 mmol) and the mixture was stirred at roomtemperature for 2.5 h. The mixture was concentrated under vacuum and theresidue triturated with 1:1 isopropyl ether/EtOAc to give a yellowsolid. The product was treated with absolute MeOH (1 mL) and 2 MHCl/Et₂O (1 mL), stirred at room temperature for 5 min and concentratedunder vacuum to give the title compound (15 mg, 36%) as a pale yellowsolid. ¹H NMR (DMSO-d₆) δ 11.04 (s, 1H), 10.57 (s, 1H), 8.41 (s, 1H),8.26 (d, 1H, J=5.6 Hz), 7.76 (dd, 1H, J=2.0, 12.7 Hz), 7.40-7.28 (m,4H), 7.19-7.14 (m, 3H), 6.54 (d, 1H, J=5.6 Hz), 3.73 (s, 2H), 2.72 (q,2H, J=7.6 Hz), 1.23 (t, 3H, J=7.6 Hz); MS (ESI⁺): m/z 412.20 (M+H)⁺.

Example 34

1-(4-(2-Amino-3-ethylpyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,trifluoroacetic acid salt

A) (4-Chloro-3-iodopyridin-2-yl)-carbamic acid tert-butyl ester

A solution of (4-chloro-pyridin-2-yl)-carbamic acid tert-butyl ester (CBResearch and Development Inc., 5.0 g, 22.0 mmol), TMEDA (8 mL) inanhydrous THF (100 mL) was placed under a nitrogen atmosphere and cooledto −70° C. and treated dropwise with 2.5 M n-BuLi in hexanes (22.0 mL,54.8 mmol) over a period of 30 min. The mixture was stirred at −70° C.for 1 h then treated dropwise with a solution of I₂ (14 g, 110 mmol) inanhydrous THF (16 mL) at −70° C. After the addition was complete, thereaction was stirred at −70° C. for 30 min then allowed to warm to roomtemperature. The mixture was treated with a solution of sodiumhydrogensulfite (16 g) in H₂O (100 mL) and stirred for 30 min thenextracted with EtOAc. The extract was washed with brine, dried (MgSO₄)and concentrated in vacuo. The product was purified by flashchromatography on SiO₂ eluting with 0-5% MeOH/CH₂Cl₂ to give the titlecompound (5.8 g, 78%) as white solid. ¹H NMR (DMSO-d₆) δ 9.46 (s, 1H),8.29 (d, 1H, J=5.6 Hz), 7.46 (d, 1H, J=5.0 Hz), 1.44 (s, 9H); MS (ESI⁻):m/z 352.99 (M−H)⁻.

B) 4-Chloro-3-iodopyridin-2-amine

A suspension of (4-chloro-3-iodo-pyridin-2-yl)-carbamic acid tert-butylester (5.6 g, 15.8 mmol) in 48% hydrobromic acid was heated at 100° C.for 10 min to give a clear solution. The mixture was cooled, treatedwith crushed ice and made basic with 6 M NaOH. The precipitated productwas collected by vacuum filtration, washed with H₂O and sucked partiallyon the funnel to give a white solid. The product was dissolved in THFand the solution dried over MgSO₄ and concentrated in vacuo to give thetitle compound (3.7 g, 93%) as a white solid. ¹H NMR (DMSO-d₆) δ 7.84(d, 1H, J=5.1 Hz), 6.73 (d, 1H, J=5.6 Hz), 6.51 (br s, 2H); MS (ESI⁺):m/z 254.97 (M+H)⁺.

C) 4-(2-Fluoro-4-nitrophenoxy)-3-iodopyridin-2-amine

A mixture of 4-chloro-3-iodopyridin-2-amine (3.6 g, 14.2 mmol) and2-fluoro-4-nitrophenol (Lancaster, 4.5 g, 28.4 mmol), DIPEA (3.6 mL,20.7 mmol) and NMP (8 mL) was placed in a glass pressure vessel andheated rapidly to 170° C. and the heating continued for 18 h. Thevolatile components were distilled off under reduced pressure and theviscous residue poured into ice-water (150 mL). The mixture wassonicated for 15 min in order to break up the gummy solid and the pH ofthe mixture was adjusted to 7.5 with saturated aq. NaHCO₃ solution. Thesolid was collected by vacuum filtration, washed with H₂O, suckedpartially dry on the funnel. The partially dried solid was suspended intoluene (150 mL) and the mixture concentrated in vacuo and the processrepeated 3 times to give a brown solid. The product was dissolved inMeOH (150 mL), treated with 4 M HCl/1,4-dioxane (8 mL) and stirred atroom temperature for 5 min and then the mixture was concentrated invacuo. The hydrochloride thus obtained was washed and triturated withEtOAc and partitioned between EtOAc and saturated aq. NaHCO₃ solution.The EtOAc phase was separated washed with brine, and then dried (MgSO₄).The EtOAc solution was treated with activated charcoal, stirred at roomtemperature for 10 min and the charcoal filtered off. The solution wasconcentrate in vacuo to give the title compound (3.9 g, 74%) as a yellowsolid. ¹H NMR (DMSO-d₆) δ 8.39 (dd, 1H, J=2.5, 10.7 Hz), 8.12 (dd, 1H,J=1.5, 9.2 Hz), 7.86 (d, 1H, J=5.6 Hz), 7.32 (dd, 1H, J=8.6, 8.6 Hz),6.40 (br s, 2H), 6.18 (d, 1H, J=5.6 Hz).

D) 4-(2-Fluoro-4-nitrophenoxy)-3-vinylpyridin-2-amine

The title compound was prepared from4-(2-fluoro-4-nitrophenoxy)-3-iodopyridin-2-amine and tributylvinyltinvia a Stille coupling reaction in the same manner as described in Step Bof Example 33. ¹H NMR (DMSO-d₆) δ 8.35 (dd, 1H, J=10.7, 3.1 Hz), 8.09(d, 1H, J=9.2 Hz), 7.85 (d, 1H, J=5.6 Hz), 7.31-7.15 (m, 1H), 6.54 (dd,1H, J=17.8, 11.7 Hz), 6.24 (br s, 2H), 6.20 (d, 1H, J=5.6 Hz), 5.71 (d,1H, J=17.8 Hz), 5.46 (d, 1H, J=11.7 Hz); MS (ESI⁺): m/z 276.17 (M+H)⁺.

E) tert-Butyl 4-(2-fluoro-4-nitrophenoxy)-3-vinylpyridin-2-ylcarbamate

A solution of 4-(2-fluoro-4-nitrophenoxy)-3-vinylpyridin-2-amine (60 mg,0.22 mmol) in 1,4-dioxane (0.5 mL) and tert-butyl alcohol (1.5 mL) wastreated with Boc₂O (140 mg, 0.64 mmol) and heated at 65° C. for 5 h. Themixture was cooled, partitioned between EtOAc and saturated aq. NaHCO₃solution. The EtOAc phase was separated, washed with brine, dried(MgSO₄) and concentrated in vacuo. The crude product was purified byflash chromatography on SiO₂ to give the title compound (50 mg, 60%) asa yellow solid. ¹H NMR (DMSO-d₆) δ 9.37 (s, 1H), 8.41 (dd, 1H, J=10.7,2.5 Hz), 8.22 (d, 1H, J=5.6 Hz), 8.15 (d, 1H, J=8.6 Hz), 7.42 (t, 1H,J=8.6 Hz), 6.86 (d, 1H, J=5.6 Hz), 6.58 (dd, 1H, J=17.8, 11.7 Hz), 5.82(d, 1H, J=16.3 Hz), 5.52 (d, 1H, J=11.7 Hz), 1.42 (s, 9H); MS (ESI⁺):m/z 376.18 (M+H)⁺.

F) tert-Butyl 4-(4-amino-2-fluorophenoxy)-3-ethylpyridin-2-ylcarbamate

A solution of tert-butyl4-(2-fluoro-4-nitrophenoxy)-3-vinylpyridin-2-ylcarbamate (48 mg, 0.13mmol) was hydrogenated over 10% palladium-carbon (10 mg) and Pt₂O (5 mg)for 1.5 h using H₂ from a rubber balloon. The mixture was filteredthrough Celite® and the filtrate concentrated in vacuo to give the titlecompound (40 mg, 89%) as a pale yellow solid. ¹H NMR (DMSO-d₆) δ 9.04(s, 1H), 8.03 (d, 1H, J=5.6 Hz), 6.95 (dd, 1H, J=8.6, 8.6 Hz), 6.50 (dd,1H, J=2.5, 13.2 Hz), 6.41 (dd, 1H, J=2.5, 9.4 Hz), 6.36 (d, 1H, J=5.6Hz), 5.44 (s, 2H), 2.67-2.62 (m, 2H), 1.43 (s, 9H), 1.11 (t, 3H, J=7.1Hz); MS (ESI⁺): m/z 348.22 (M+H)⁺.

G) tert-Butyl3-ethyl-4-(2-fluoro-4-(3-(2-(4-fluorophenyl)acetyl)ureido)phenoxy)pyridin-2-ylcarbamate

The title compound was prepared from tert-butyl4-(4-amino-2-fluorophenoxy)-3-ethylpyridin-2-ylcarbamate (20 mg, 0.058mmol) and 0.3 M solution of 2-(4-fluorophenyl)acetyl isocyanate intoluene (232 μL, 0.070 mmol) in THF in the same manner as Step D ofExample 33. MS (ESI⁺): m/z 527.31 (M+H)⁺.

H)1-(4-(2-Amino-3-ethylpyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,trifluoroacetic acid salt

A solution of tert-butyl3-ethyl-4-(2-fluoro-4-(3-(2-(4-fluorophenyl)acetyl)ureido)phenoxy)pyridin-2-ylcarbamate(16 mg, 0.03 mmol) was dissolved in anhydrous THF (0.5 mL) and treatedwith 4 M HCl/1,4-dioxane (1.5 mL) and stirred at room temperature for 3h. The mixture was concentrated in vacuo and the product purified bypreparative HPLC method A to give the title compound (5 mg, 36%) as awhite solid. ¹H NMR (DMSO-d₆) δ 11.06 (s, 1H), 10.6 (s, 1H), 7.80-7.79(m, 4H), 7.43-7.33 (m, 4H), 7.16 (dd, 2H, J=8.9, 8.9 Hz), 6.19 (d, 1H,J=7.1 Hz), 3.73 (s, 2H), 2.71-2.66 (m, 2H), 1.10 (t, 3H, J=7.1 Hz); MS(ESI⁺): m/z 427.18 (M+H)⁺.

Example 35

1-(4-(3-(2-(4-Aminocyclohex-1-enyl)ethynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea

A) 4-(tert-Butoxycarbonyl)cyclohex-1-enyl trifluoromethanesulfonate

A solution of N-Boc-4-aminocyclohexanone (Astatech Inc., 213 mg, 1.0mmol) in THF (7 mL) was cooled to −70° C. and treated with a solution0.5 M KHMDS in toluene (2.4 ml, 1.2 mmol). The mixture was stirred at−70° C. for 20 min, treated dropwise with a solution ofphenyltrifluoromethanesulfonimide (392 mg, 1.1 mmol) in THF (4 mL) andstirred at −70° C. for 25 min. The mixture was quenched with saturatedaq. NH₄Cl solution, diluted with EtOAc, washed with 10% Na₂CO₃ andbrine, dried (MgSO₄) and concentrated in vacuo. The crude product waspurified by flash chromatography on SiO₂ eluting with 10-25%EtOAc/hexanes to give the title compound (180 mg, 52%) as a white solid.¹H NMR (DMSO-d₆) δ 5.68 (s, 1H), 4.50 (s, 1H), 3.82 (s, 1H), 2.68-2.25(m, 3H), 2.22-1.89 (m, 2H), 1.87-1.63 (m, 1H), 1.43 (s, 9H).

B) tert-Butyl 4-(2-(trimethylsilyl)ethynyl)cyclohex-3-enylcarbamate

A mixture of 4-(tert-butoxycarbonyl)cyclohex-1-enyltrifluoromethanesulfonate (170 mg, 0.49 mmol), trimethylsilylacetylene(138 μL, 0.98 mmol), Et₃N (0.68 mL) and THF (8 mL) in a reaction flaskwas purged with argon and treated in turn with CuI (14 mg, 0.072 mmol)and (Ph₃P)₄Pd (27 mg, 0.024 mmol). The reaction mixture was stirred atroom temperature for 25 min, and then diluted with EtOAc (50 mL), washedwith saturated aq. NaHCO₃ solution and brine, dried (MgSO₄) andconcentrated in vacuo. The crude product was purified by flashchromatography on SiO₂ eluting with 0-25% EtOAc/hexanes to give thetitle compound (116 mg, 81%) as a yellow solid. ¹H NMR (DMSO-d₆) δ 6.06(s, 1H), 4.50 (s, 1H), 3.76 (s, 1H), 2.46 (d, 1H, J=18.8 Hz), 2.36-2.14(m, 2H), 2.00-1.78 (m, 2H), 1.66-1.50 (m, 1H), 1.43 (s, 9H), 0.27-0.05(m, 9H).

C) tert-Butyl 4-ethynylcyclohex-3-enylcarbamate

A solution of tert-butyl4-(2-(trimethylsilyl)ethynyl)cyclohex-3-enylcarbamate (112 mg, 0.38mmol) in THF was cooled to −15° C., treated with 1.0 Mtetrabutylammonium fluoride in THF (Aldrich, 440 μL, 0.44 mmol) and themixture stirred at −15° C. for 40 min. The mixture was treated with 5%Na₂CO₃ (25 mL) and extracted with ether. The ether extract was washedwith 5% Na₂CO₃ and brine, dried (MgSO₄) and concentrated in vacuo togive the title compound (83 mg, 99%) as a brown oil. ¹H NMR (DMSO-d₆) δ6.09 (s, 1H), 4.51 (s, 1H), 3.77 (s, 1H), 2.82 (s, 1H), 2.47 (d, 1H,J=18.3 Hz), 2.35-2.16 (m, 2H), 2.04-1.79 (m, 2H), 1.72-1.51 (m, 1H),1.43 (s, 9H).

D) tert-Butyl4-(2-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)ethynyl)cyclohex-3-enylcarbamate

A solution of 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridine (Compound A ofExample 33, 130 mg, 0.36 mmol) and N-Boc-4-ethynylcyclohex-3-enamine (80mg, 0.36 mmol) in anhydrous THF (2 mL) was treated with Et₃N (2 mL) andthe degassed by vacuum/argon purge. The solution was treated withtetrakistriphenylphosphine palladium (20 mg, 0.0018 mmol) and CuI (10mg, 0.054 mmol) and then heated at reflux for 2 h. The mixture wascooled and partitioned between saturated aq. NaHCO₃ solution and EtOAc.The EtOAc phase was separated, washed with brine, dried (MgSO₄) andconcentrated in vacuo. The crude product was purified by flashchromatography on silica gel eluting with 0-40% EtOAc/hexanes to givethe title compound (124 mg, 76%) as a yellow solid. ¹H NMR (DMSO-d₆) δ8.68 (s, 1H), 8.51 (d, 1H, J=5.6 Hz), 8.43 (dd, 1H, J=2.5, 10.7 Hz),8.15 (d, 1H, J=9.2 Hz), 7.49 (dd, 1H, J=8.6, 8.6 Hz), 7.14 (d, 1H, J=5.6Hz), 6.85 (d, 1H, J=7.1 Hz), 6.04-6.00 (m, 1H), 3.48-3.35 (m, 1H),2.36-2.25 (m, 1H), 2.17-2.04 (m, 2H), 2.03-1.89 (m, 1H), 1.78-1.69 (m,1H), 1.46-1.35 (m, 1H), 1.36 (s, 9H); MS (ESI⁺): m/z 454.27 (M+H)⁺.

E) tert-Butyl4-(2-(4-(4-amino-2-fluorophenoxy)pyridin-3-yl)ethynyl)cyclohex-3-enylcarbamate

A mixture of tert-butyl4-(2-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)ethynyl)cyclohex-3-enylcarbamate(110 mg, 0.24 mmol), iron powder, ˜325 mesh (150 mg, 2.7 mmol), NH₄Cl(280 mg, 5.3 mmol), DMF (1 mL), H₂O (1 mL) and EtOH (1 mL) was heated at100° C. for 30 minutes. The mixture was filtered through a pad ofCelite® using DMF to wash the filter cake and the filtrate made basic topH 8 with saturated aq. NaHCO₃ solution. The mixture was extracted twicewith EtOAc and dried (MgSO₄) and concentrated in vacuo to give the titlecompound (105 mg) which was used without any further purification. MS(ESI⁺): m/z 424.27 (M+H)⁺.

F) tert-Butyl4-(2-(4-(2-fluoro-4-(3-(2-(4-fluorophenyl)acetyl)ureido)phenoxy)pyridin-3-yl)ethynyl)cyclohex-3-enylcarbamate

A solution of tert-butyl4-(2-(4-(4-amino-2-fluorophenoxy)pyridin-3-yl)ethynyl)cyclohex-3-enylcarbamate(50 mg, 0.12 mmol) in dry CH₂Cl₂ (2 mL) was treated with a 0.3 Msolution of 2-(4-fluorophenyl)acetyl isocyanate in toluene (Compound Dof Example 11, 0.8 mL, 0.24 mmol) and the mixture stirred at rt for 1 h.The solvents were evaporated under vacuum and the residue purified byflash chromatography on silica gel eluting with 10-60% EtOAc/hexanes togive the title compound (50 mg, 69%) as a white solid. ¹H NMR (DMSO-d₆)δ 11.03 (s, 1H), 10.57 (s, 1H), 8.57 (s, 1H), 8.36 (d, 1H, J=5.7 Hz),7.78 (dd, 1H, J=1.8, 13.1 Hz), 7.41-7.29 (m, 3H), 7.16 (dd, 3H, J=8.6,8.6 Hz), 6.85 (d, 1H, J=8.3 Hz), 6.70 (d, 1H, J=5.7 Hz), 6.13-6.08 (m,1H), 3.73 (s, 2H), 3.51-3.41 (m, 1H), 2.38-2.27 (m, 1H), 2.27-2.20 (m,2H), 1.82-1.72 (m, 1H), 1.54-1.28 (m, 2H), 1.37 (s, 9H); ESI MS): m/z603.24 (M+H)⁺.

G)1-(4-(3-(2-(4-Aminocyclohex-1-enyl)ethynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,dihydrochloride salt

A solution of tert-butyl4-(2-(4-(2-fluoro-4-(3-(2-(4-fluorophenyl)acetyl)ureido)phenoxy)pyridin-3-yl)ethynyl)cyclohex-3-enylcarbamate(40 mg, 0.066 mol) in anhydrous 1,4-dioxane (2 mL) was cooled to −10° C.and treated with 4 M HCl/1,4-dioxane (4 mL). The mixture was stirred at−5° C. for 2.5 h then at rt for 1 h. The mixture was concentrated undervacuum without any heating to give the title compound (32 mg, 84%) as ayellow solid. ¹H NMR (DMSO-d₆) δ 11.05 (s, 1H), 10.61 (s, 1H), 8.69 (s,1H), 8.44 (d, 1H, J=6.1 Hz), 8.06 (d, 1H, J=2.0 Hz), 7.80 (dd, 1H,J=12.7, 2.0 Hz), 7.46-7.38 (m, 1H), 7.35 (dd, 1H, J=8.6, 5.6 Hz),7.19-7.13 (m, 1H), 6.82 (d, 1H, J=5.6 Hz), 6.17 (s, 1H), 3.74 (s, 2H),3.73-3.62 (m, 2H), 3.62-3.54 (m, 1H), 3.34-3.22 (m, 1H), 2.31 (s, 1H),1.99-1.96 (m, 1H), 1.71-1.66 (m, 1H); MS (ESI⁺): m/z 503.12 (M+H)⁺.

Example 36

1-(4-(3-(3-(3-(Aminomethyl)azetidin-1-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,trihydrochloride salt

A) 3-(4-(2-Fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-yn-1-ol

A solution of 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridine (Compound A ofExample 33, 300 mg, 0.83 mmol), propargylalcohol (Aldrich, 145 μL, 2.50mmol), Et₃N (2 mL) and anhydrous THF (2 mL) was degassed by vacuum/argonpurge and treated with Pd(Ph₃P)₄ (31 mg, 0.027 mmol) and CuI (10 mg,0.054 mmol). The mixture was heated at reflux under argon atmosphere for10 min, cooled to rt and diluted with EtOAc (25 mL) and H₂O (20 mL). TheEtOAc phase was washed with water and brine, dried (MgSO₄) andconcentrated in vacuo. The crude residue was purified by flashchromatography on silica gel using 0-3% MeOH/CH₂Cl₂ to give the desiredproduct (185 mg, 77%) as a pale yellow solid. ¹H NMR (DMSO-d₆) δ 8.69(s, 1H), 8.49 (d, 1H, J=5.6 Hz), 8.43 (dd, 1H, J=10.7, 2.5 Hz), 8.17 (d,1H, J=9.2 Hz), 7.57 (t, 1H, J=8.6 Hz), 7.04 (d, 1H, J=5.6 Hz), 5.40 (t,1H, J=6.1), 4.28 (d, 2H, J=6.1 Hz); MS (ESI⁺): m/z 289.13 (M+H)⁺.

B) tert-Butyl(1-(3-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-ynyl)azetidin-3-yl)methylcarbamate

A solution of 3-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-yn-1-ol(43 mg, 0.15 mmol) and DIPEA (45 μL, 0.26 mmol) in anhydrous THF (1.5mL) was cooled to 0° C. and treated with methanesulfonyl chloride (15mg, 0.11 mmol) in portions. After stirring at 0° C. for 1 h, the mixturewas concentrated under reduced pressure. The residue was treated withDMF (1.0 mL), DIPEA (45 μL, 0.26 mmol) and azetidin-3-ylmethyl-carbamicacid tert-butyl ester (Beta Pharma Inc., 145 mg, 0.78 mmol) and stirredat rt for 2 h. The reaction mixture was partitioned between EtOAc andsaturated aq. NaHCO₃ solution and the EtOAc phase separated, washed withbrine dried (MgSO₄) and concentrated in vacuo. The residue was purifiedby flash chromatography on SiO₂ eluting with 1-5% MeOH/CH₂Cl₂ to affordthe title compound (33 mg, 48%) as a colorless oil. ¹H NMR (DMSO-d₆) δ8.74 (s, 1H), 8.51 (d, 1H, J=5.6 Hz), 8.41 (dd, 1H, J=10.7, 2.5 Hz),8.15 (d, 1H, J=9.2 Hz), 7.53 (t, 1H, J=8.6 Hz), 7.09 (d, 1H, J=6.1 Hz),6.86 (t, 1H, J=5.6 Hz), 3.39 (s, 2H), 3.24-3.14 (m, 2H), 3.07-2.98 (m,2H), 2.94-2.87 (m, 2H), 2.37-2.26 (m, 1H), 1.33 (s, 9H); MS (ESI⁺): m/z401.20 (100), [(M-C₄H₉)]⁺; m/z 457.20 (25), (M+H)⁺.

C) tert-Butyl(1-(3-(4-(4-amino-2-fluorophenoxy)pyridin-3-yl)prop-2-ynyl)azetidin-3-yl)methylcarbamate

The title compound was prepared by the reduction of tert-butyl(1-(3-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-ynyl)azetidin-3-yl)methylcarbamate(30 mg, 0.66 mmol) in the same manner as in Step E of Example 35 usingFe powder (50 mg, 0.091 mmol) and NH₄Cl (96 mg, 1.82 mmol). The productwas used in subsequent reactions without any purification. MS (ESI⁺):m/z 371.24 (100), [(M-C₄H₉)]⁺; m/z 427.27 (25), (M+H)⁺.

D) tert-Butyl(1-(3-(4-(2-fluoro-4-(3-(2-(4-fluorophenyl)acetyl)ureido)phenoxy)pyridin-3-yl)prop-2-ynyl)azetidin-3-yl)methylcarbamate

The title compound was prepared from tert-butyl(1-(3-(4-(4-amino-2-fluorophenoxy)pyridin-3-yl)prop-2-ynyl)azetidin-3-yl)methylcarbamate(25 mg, 0.059 mmol) and a 0.3 M solution of 2-(4-fluorophenyl)acetylisocyanate in toluene (Compound D of Example 11, 0.37 mL, 0.11 mmol) inthe same manner as Step D of Example 33 to give the title compound as awhite solid (20 mg, 57%). ¹H NMR (DMSO-d₆) δ 11.04 (s, 1H), 10.58 (s,1H), 8.63 (s, 1H), 8.37 (d, 1H, J=5.5 Hz), 7.78 (d, 1H, J=12.6 Hz),7.40-7.33 (m, 4H), 7.16 (dd, 2H, J=8.8, 8.9 Hz), 6.89-6.87 (m, 1H), 6.68(d, 1H, J=5.5 Hz), 3.73 (s, 2H), 3.45 (s, 2H), 3.26-3.24 (m, 2H),3.07-3.04 (m, 2H), 2.98-2.96 (m, 2H), 2.38-2.35 (m, 2H), 1.32 (s, 9H);MS (ESI⁺): m/z 606.26 (M+H)⁺.

E)1-(4-(3-(3-(3-(Aminomethyl)azetidin-1-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,trihydrochloride salt

tert-Butyl(1-(3-(4-(2-fluoro-4-(3-(2-(4-fluorophenyl)acetyl)ureido)phenoxy)pyridin-3-yl)prop-2-ynyl)azetidin-3-yl)methylcarbamate(20 mg, 0.033 mmol) was dissolved in CH₂Cl₂ (2 mL) and treated with TFA(0.5 mL) and the mixture stirred at room temperature for 1.5 h. Themixture was concentrated in vacuo and purified by preparative HPLC(Column A) to give the TFA salt. The TFA salt was dissolved in absoluteMeOH and treated with 1.0 M HCl/ether stirred for 5 min and concentratedin vacuo to give the title compound (9 mg, 45%) as a white solid. ¹H NMR(DMSO-d₆) δ 11.07 (s, 1H), 10.06 (s, 1H), 8.96 (m, 1H), 8.61-8.52 (m,1H), 8.36-8.25 (s, 2H), 7.82 (d, 1H, J=12.2 Hz), 7.45-7.42 (m, 2H),7.37-7.33 (m, 2H), 7.18-7.14 (m, 2H), 6.92 (d, 1H, J=6.1 Hz), 4.48 (s,2H), 4.27-3.98 (m, 2H), 3.76 (s, 2H), 3.30-3.20 (m, 1H), 3.16-3.00 (m,2H); MS (ESI⁺): m/z 506.18 (M+H)⁺.

Examples 37-40 were prepared in a similar manner to that which isdescribed in Example 36.

Example 37

1-(4-(3-(3-(3-Aminoazetidin-1-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,trihydrochloride salt

MS (ESI⁺): m/z 492.17 (M+H)⁺

Example 38

1-(3-Fluoro-4-(3-(3-(piperazin-1-yl)prop-1-ynyl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea,trihydrochloride salt

¹H NMR (DMSO-d₆) δ 11.07 (s, 1H), 10.63 (s, 1H), 9.44 (s, 1H), 8.91 (s,1H), 8.50 (d, 1H, J=6.2 Hz), 7.84-7.78 (m, 1H), 7.45-7.39 (m, 2H),7.38-7.32 (m, 2H), 7.16 (t, 2H, J=8.8 Hz), 6.85 (d, 1H, J=6.2 Hz), 4.26(s, 2H), 3.75 (s, 2H), 3.34 (br s, 4H), 2.49 (br s, 4H); MS (ESI⁺): m/z506.23 (M+H)⁺.

Example 39

1-(4-(3-(3-(4-Aminopiperidin-1-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,trihydrochloride salt

¹H NMR (DMSO-d₆) δ 11.07 (s, 1H), 10.62 (s, 1H), 8.81 (s, 1H), 8.48 (d,1H, J=6.1 Hz), 8.31 (s, 2H), 7.80 (dd, 1H, J=2.2, 12.7 Hz), 7.44-7.33(m, 4H), 7.19-7.13 (m, 2H), 6.78 (d, 1H, J=5.7 Hz), 4.40 (s, 2H), 3.74(s, 2H), 3.64-3.60 (m, 2H), 3.34-3.22 (m, 1H), 3.19-3.13 (m, 2H),2.16-2.13 (m, 2H), 1.99-1.88 (m, 2H); MS (ESI⁺): m/z 506.23 (M+H)⁺.

Example 40

(±)-1-(4-(3-(3-(3-Aminopyrrolidin-1-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,trihydrochloride salt

¹H NMR (DMSO-d₆) δ 11.08 (s, 1H), 10.65 (s, 1H), 8.96 (s, 1H), 8.54 (d,1H, J=6.1 Hz), 7.83 (d, 1H, J=12.7 Hz), 7.43 (s, 2H), 7.37-7.33 (m, 2H),7.16-7.14 (m, 2H), 6.90 (d, 1H, J=5.6 Hz), 4.62 (s, 2H), 4.06-3.87 (m,1H), 3.75 (s, 2H), 3.70-3.55 (m, 3H), 3.49-3.44 (m, 2H), 2.25-2.08 (m,1H); MS (ESI⁺): m/z 506.22 (M+H)⁺.

Example 41

1-(3-Fluoro-4-(3-(3-((3R,4R)-3-hydroxy-4-(pyrrolidin-1-yl)pyrrolidin-1-yl)prop-1-ynyl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea,trihydrochloride salt

A)(3R,4R)-1-(3-(4-(2-Fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-ynyl)-4-(pyrrolidin-1-yl)pyrrolidin-3-ol

A solution of 3-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-yn-1-ol(Compound A of Example 36, 43 mg, 0.15 mmol) and DIPEA (45 μL, 0.26mmol) in anhydrous THF (1.5 mL) was cooled to 0° C. and treated withmethanesulfonyl chloride (15 mg, 0.11 mmol) in portions. After stirringat 0° C. for 1 h, the mixture was concentrated under reduced pressure.The residue was treated with DMF (1.0 mL), DIPEA (45 μL, 0.26 mmol) and(3R,4R)-4-(pyrrolidin-1-yl)pyrrolidin-3-ol (Lexicon PharmaceuticalCorp., 94 mg, 0.6 mmol) and stirred at rt for 2 h. The reaction mixturewas partitioned between EtOAc and saturated aq. NaHCO₃ solution and theEtOAc phase separated, washed with brine, dried (MgSO₄) and concentratedin vacuo. The crude product was purified by flash chromatography on SiO₂eluting with 0-1.5% MeOH/CH₂Cl₂ to give the title compound (38 mg, 59%)as a brown oil. ¹H NMR (DMSO-d₆) δ 8.72 (s, 1H), 8.54 (d, 1H, J=5.6 Hz),8.40 (dd, 1H, J=10.7, 2.5 Hz), 8.14 (d, 1H, J=9.2 Hz), 7.43 (t, 1H,J=8.6 Hz), 7.15 (d, 1H, J=5.6 Hz), 4.99-4.81 (m, 1H), 4.11-4.10 (m,0.5H), 3.92-3.84 (m, 1H), 3.54 (s, 2H), 3.59-3.50 (m, 0.5H), 3.16-3.15(m, 1H), 2.79-2.75 (m, 1H), 2.60-2.32 (m, 4H), 1.70-1.59 (m, 4H); MS(ESI⁺): m/z 427.24 (M+H)⁺.

B)(3R,4R)-1-(3-(4-(4-Amino-2-fluorophenoxy)pyridin-3-yl)prop-2-ynyl)-4-(pyrrolidin-1-yl)pyrrolidin-3-ol

A mixture of(3R,4R)-1-(3-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-ynyl)-4-(pyrrolidin-1-yl)pyrrolidin-3-ol(35 mg, 0.082 mmol), DMF (1 mL), EtOH (1 mL) and H₂O (1 mL) was treatedwith Fe powder (67 mg, 1.2 mmol, 2.4 mmol) and heated at 100° C. for 45min. The mixture was filtered through Celite®, made basic with NaHCO₃and concentrate in vacuo. The residue was partitioned between EtOAc andsaturated aq. NaHCO₃ solution. The EtOAc phase was dried (MgSO₄) andconcentrated in vacuo to give the crude aniline (16 mg, 50%) which wasused directly in the next step without further purification. MS (ESI⁺):m/z 397.28 (M+H)⁺.

C)1-(3-Fluoro-4-(3-(3-((3R,4R)-3-hydroxy-4-(pyrrolidin-1-yl)pyrrolidin-1-yl)prop-1-ynyl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea,trihydrochloride salt

The title compound was prepared from(3R,4R)-1-(3-(4-(4-amino-2-fluorophenoxy)pyridin-3-yl)prop-2-ynyl)-4-(pyrrolidin-1-yl)pyrrolidin-3-ol(16 mg, 0.04 mmol) and a 0.3 M solution of 2-(4-fluorophenyl)acetylisocyanate in toluene (Compound D of Example 11, 0.13 mL, 0.04 mmol) ina manner similar to that of Step D of Example 33. The product waspurified by preparative HPLC (Column A) and converted to thehydrochloride salt in the same manner as in Step E of Example 36 to givethe title compound (9 mg, 33%) as a white solid. ¹H NMR (DMSO-d₆) δ11.06 (s, 1H), 10.62 (s, 1H), 8.86 (s, 1H), 8.45 (d, 1H, J=6.1 Hz), 7.81(d, 1H, J=12.2 Hz), 7.45-7.40 (m, 4H), 7.33-7.28 (m, 4H), 7.16 (dd, 2H,J=9.2, 8.6 Hz), 6.80 (d, 1H, J=6.1 Hz), 4.64 (s, 1H), 4.34 (s, 2H),3.84-3.70 (m, 4H), 2.70-3.55 (m, 2H), 3.55-2.98 (m, 3H), 2.08-1.92 (m,2H), 1.92-1.75 (m, 2H); MS (ESI⁺): m/z 576.25 (M+H)⁺.

Example 42

1-(3-Fluoro-4-(3-(3-(2-(pyrrolidin-1-yl)acetamido)prop-1-ynyl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea,dihydrochloride salt

A) N-Boc-propargylamine

Di-tert-butyl-dicarbonate (21.8 mg, 100.0 mmol) was dissolved in THF (25mL) and the solution cooled to 0° C. and treated dropwise with asolution of propargylamine (Aldrich, 5.0 g, 90.0 mmol) keeping thetemperature below 15° C. The mixture was stirred at rt for 1.5 h thenconcentrated under vacuum. The residue was dissolved in hexanes andfiltered through a column of silica gel using 0-100% CH₂Cl₂/hexanes toelute the product. The eluent containing the product was concentrated invacuo to give a colorless oil which was dissolved in hexanes (150 mL)and cooled to 0° C. to give white crystals. The crystals were collectedby filtration and dried under vacuum to give the title compound (10.5 g,75%). ¹H NMR (CDCl₃) δ 4.75 (s, 1H), 3.95 (s, 2H), 2.25-2.24 (m, 1H),1.48 (s, 9H).

B) tert-Butyl3-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-ynylcarbamate

The title compound was prepared from N-Boc-propargylamine (98 mg, 0.63mmol) and 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridine (Compound A ofExample 33, 150 mg, 0.42 mmol) via a Sonagashira cross coupling reactionusing Pd(Ph₃P)₄ (9 mg, 0.008 mmol) and CuI (1.5 mg, 0.008 mmol) in 1:1Et₃N/THF (3 mL) according to Step C of Example 35. The title compound(124 mg, 76%) was obtained as a red oil. ¹H NMR (DMSO-d₆) δ 8.66 (s,1H), 8.50 (d, 1H, J=5.6 Hz), 8.40 (dd, 1H, J=2.5, 10.7 Hz), 8.15 (d, 1H,J=9.2 Hz), 7.52 (dd, 1H, J=8.1, 8.6 Hz), 7.33-7.30 (m, 1H), 7.07 (d, 1H,J=5.6 Hz), 3.95 (d, 2H, J=5.6 Hz), 1.35 (s, 9H); MS (ESI⁺): m/z 388.21(M+H)⁺.

C) 3-(4-(2-Fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-yn-1-amine

A solution of tert-butyl3-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-ynylcarbamate (300 mg,0.78 mmol) in CH₂Cl₂ (10 mL) was treated with TFA (2 mL) and stirred atrt for 45 min. The mixture was concentrated under vacuum and the residuewas partitioned between EtOAc and saturated aq. NaHCO₃ solution. TheEtOAc phase was separated and washed with brine, dried (MgSO₄) andconcentrated in vacuo to give the title compound (180 mg, 80%) as a redoil. ¹H NMR (DMSO-d₆) δ 8.65 (s, 1H), 8.47 (d, 1H, J=5.6 Hz), 8.43 (dd,1H, J=10.7, 2.5 Hz), 8.17 (d, 1H, J=8.6 Hz), 7.54 (t, 1H, J=8.6 Hz),7.04 (d, 1H, J=5.6 Hz), 3.49 (s, 2H); MS (ESI⁺): m/z 288.17 (M+H)⁺.

D)N-(3-(4-(2-Fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-ynyl)-2-(pyrrolidin-1-yl)acetamide

A solution of3-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-yn-1-amine (80 mg,0.26 mmol) in anhydrous CH₂Cl₂ (2.5 mL) was cooled to 0° C. and treatedwith chloroacetyl chloride (40 mg, 0.37 mmol) the mixture was stirred atrt for 1 h. The mixture was concentrated under vacuum to removed thesolvent and excess reagent and the residue redissolved in CH₃CN (1.5mL), treated with pyrrolidone (55 mg, 0.78 mmol) and stirred at rt for 4h. The mixture was partitioned between EtOAc and saturated aq. NaHCO₃solution and the organic phase separated, washed with brine, dried(MgSO₄) and concentrated to give crude product. The residue was purifiedby flash chromatography on silica gel eluting with 0-10% MeOH/CH₂Cl₂ toafford the title compound (40 mg, 39%) as a brown oil. ¹H NMR (DMSO-d₆)δ 8.66 (s, 1H), 8.50 (d, 1H, J=6.1 Hz), 8.41 (dd, 1H, J=2.8, 10.4 Hz),8.18-8.15 (m, 2H), 7.51 (dd, 1H, J=8.3, 8.8 Hz), 7.06 (d, 1H, J=5.5 Hz)4.10 (d, 2H, J=5.5 Hz), 3.01 (s, 2H), 2.47-2.43 (m, 4H), 1.67-1.63 (m,4H); MS (ESI⁺): m/z 399.27 (M+H)⁺.

E)N-(3-(4-(4-Amino-2-fluorophenoxy)pyridin-3-yl)prop-2-ynyl)-2-(pyrrolidin-1-yl)acetamide

The title compound was prepared by the reduction ofN-(3-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-ynyl)-2-(pyrrolidin-1-yl)acetamide(35 mg, 0.088 mmol) in the manner similar to that of Step E of Example35 using Fe powder (67 mg, 1.21 mmol) and NH₄Cl (128 mg, 2.42 mmol). Theproduct was used in subsequent reactions without any purification.Yellow oil (30 mg, 93%). MS (ESI⁺): m/z 319.24 (M+H)⁺.

F)1-(3-Fluoro-4-(3-(3-(2-(pyrrolidin-1-yl)acetamido)prop-1-ynyl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea,dihydrochloride salt

The title compound was prepared fromN-(3-(4-(4-amino-2-fluorophenoxy)pyridin-3-yl)prop-2-ynyl)-2-(pyrrolidin-1-yl)acetamide(32 mg, 0.088 mmol) and 0.3 M solution of 2-(4-fluorophenyl)acetylisocyanate in toluene (Compound D of Example 11, 0.40 ml, 0.12 mmol)using THF (0.5 ml) in a manner similar to that of Step D of Example 33.The product was purified by preparative HPLC (Column B). The fractioncontaining the product was treated with excess 1 M hydrochloric acid,concentrated in vacuo and lyophilized to give the title compound (30 mg,63%) as a pale yellow solid. ¹H NMR (DMSO-d₆) δ 11.07 (s, 1H), 10.62 (s,1H), 10.09 (s, 1H), 9.17-9.14 (m, 1H), 8.65 (s, 1H), 8.43 (d, 1H, J=5.6Hz), 7.81 (dd, 1H, J=2.5, 12.7 Hz), 7.44-7.33 (m, 4H), 7.19-7.12 (m,2H), 4.31 (d, 2H, J=5.6 Hz), 4.05 (d, 2H, J=5.6 Hz), 3.74 (s, 2H),3.56-3.51 (m, 2H), 3.05-2.99 (m, 2H), 1.96-1.90 (m, 2H), 1.88-1.79 (m,2H); MS (ESI⁺): m/z 548.26 (M+H)⁺.

Example 43

1-(3-Fluoro-4-(3-(3-(2-(4-hydroxypiperidin-1-yl)acetamido)prop-1-ynyl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea,dihydrochloride salt

A)N-(3-(4-(2-Fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-ynyl)-2-(4-hydroxypiperidin-1-yl)acetamide

The title compound was prepared from3-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-yn-1-amine (Compound Aof Example 36, 80 mg, 0.26 mmol), 4-hydroxypiperidine (79 mmol, 0.78mmol) and chloroacetyl chloride (40 mg, 0.36 mmol) in the same manner asfor Step D of Example 42. The residue was purified by flashchromatography on silica gel eluting with 1-3% MeOH/CH₂Cl₂ to give awhite foam (40 mg, 36%). ¹H NMR (DMSO-d₆) δ 8.65 (s, 1H), 8.49 (d, 1H,J=5.5 Hz), 8.41 (dd, 1H, J=10.4, 2.7 Hz), 8.18-8.12 (m, 2H), 7.55-7.50(m, 1H), 7.05 (d, 1H, J=6.0 Hz), 4.54 (d, 1H, J=3.8 Hz), 4.11 (d, 2H,J=6.0 Hz), 3.43-3.36 (m, 1H), 2.86 (s, 2H), 2.64-2.58 (m, 2H), 2.12-2.05(m, 2H), 1.67-1.61 (m, 2H), 1.44-1.36 (m, 2H); MS (ESI⁺): m/z 429.18(M+H)⁺.

B)N-(3-(4-(4-Amino-2-fluorophenoxy)pyridin-3-yl)prop-2-ynyl)-2-(4-hydroxypiperidin-1-yl)acetamide

The title compound was prepared by the reductionN-(3-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-ynyl)-2-(4-hydroxypiperidin-1-yl)acetamide(33 mg, 0.077 mmol) in a manner similar to that of Step E of Example 35using Fe (powder, 67 mg, 1.21 mmol), NH₄Cl (128 mg, 2.42 mmol). Theproduct (30 mg, 100%) was obtained as a yellow oil which was useddirectly in the subsequent step. MS (ESI⁺): m/z 399.27 (M+H)⁺.

C)1-(3-Fluoro-4-(3-(3-(2-(4-hydroxypiperidin-1-yl)acetamido)prop-1-ynyl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea,dihydrochloride salt

The title compound was prepared fromN-(3-(4-(4-amino-2-fluorophenoxy)pyridin-3-yl)prop-2-ynyl)-2-(4-hydroxypiperidin-1-yl)acetamide(25 mg, 0.063 mmol) and 0.3 M solution of 2-(4-fluorophenyl)acetylisocyanate in toluene (Compound D of Example 11, 0.40 mL, 0.12 mmol)using THF (0.5 ml) in a manner similar to that of Step D of Example 33.The product was purified by preparative HPLC (Column B). The fractioncontaining the product was treated with excess 1 N hydrochloric acid,concentrated and lyophilized to give the title compound (10 mg, 30%) asa pale yellow solid. ¹H NMR (DMSO-d₆) δ 11.08 (s, 1H), 10.64 (s, 1H),9.83-9.72 (m, 1H), 9.25-9.20 (m, 1H), 8.66 (s, 1H), 8.45 (d, 1H, J=6.1Hz), 7.83 (dd, 1H, J=2.0, 13.2 Hz), 7.46-7.35 (m, 3H), 7.21-7.11 (m,2H), 6.77 (d, 1H, J=6.1 Hz), 4.33-4.31 (m, 2H), 3.99-3.94 (m, 2H),3.92-3.89 (m, 1H), 3.76 (s, 2H), 3.46-3.40 (m, 2H), 3.29-3.21 (m, 2H),3.10-3.00 (m, 1H), 1.98-1.87 (m, 2H), 1.72-1.62 (m, 2H); MS (ESI⁺): m/z528.25 (M+H)⁺.

Example 44

(S)-1-(3-Fluoro-4-(3-(3-(2-(pyrrolidin-1-ylmethyl)pyrrolidine-1-carboxamido)prop-1-ynyl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea,dihydrochloride salt

A)(S)—N-(3-(4-(2-Fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-ynyl)-2-(pyrrolidin-1-ylmethyl)pyrrolidine-1-carboxamide

3-(4-(2-Fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-yn-1-amine (Compound Aof Example 36, 55 mg, 0.19 mmol) was dissolved in CH₂Cl₂ (5 mL), treatedwith 4-nitrophenyl chloroformate (0.38 mg, 0.19 mmol) and pyridine (15μL, 0.19 mmol). The reaction mixture was stirred at rt. After 1 h, themixture was treated with Et₃N (30 mL, 0.20 mmol) and(s)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidone (Aldrich, 32 mg, 0.21 mmol)and stirred at rt for 15 h. The mixture was then diluted with CH₂Cl₂ (50mL), washed with 1 M NaOH and brine, dried (MgSO₄) and concentrated invacuo to give the crude product. The residue was purified by flashchromatography on silica gel eluting with 0-10% MeOH/CH₂Cl₂ to give thetitle compound (53 mg, 60%) as a yellow oil. ¹H NMR (DMSO-d₆) δ 8.65 (s,1H), 8.49 (d, 1H, J=6.1 Hz), 8.41 (dd, 1H, J=2.8 Hz, 10.5 Hz), 8.16 (d,1H, J=7.7 Hz), 7.52 (dd, 1H, J=8.3, 8.8 Hz), 7.05 (d, 1H, J=6.1 Hz),4.11-4.06 (m, 2H), 3.99-3.95 (m, 2H), 3.76 (s, 2H), 3.16-3.11 (m, 2H),2.57-2.48 (m, 2H), 2.43-2.41 (m, 2H), 3.36-2.34 (m, 2H), 1.90-1.86 (m,2H), 1.76-1.62 (m, 3H); MS (ESI⁺): m/z 468.27 (M+H)⁺.

B)(S)—N-(3-(4-(4-Amino-2-fluorophenoxy)pyridin-3-yl)prop-2-ynyl)-2-(pyrrolidin-1-ylmethyl)pyrrolidine-1-carboxamide

The title compound was prepared by the reductionof(S)—N-(3-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-ynyl)-2-(pyrrolidin-1-ylmethyl)pyrrolidine-1-carboxamide(50 mg, 0.11 mmol) in a manner similar to that of Step E of Example 35using Fe (powder, 67 mg, 1.21 mmol), NH₄Cl (128 mg, 2.42 mmol). Theproduct (36 mg, 75%) was obtained as a yellow oil which was useddirectly in the subsequent step. MS (ESI⁺): m/z 438.30 (M+H)⁺.

C)(S)-1-(3-Fluoro-4-(3-(3-(2-(pyrrolidin-1-ylmethyl)pyrrolidine-1-carboxamido)prop-1-ynyl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea,dihydrochloride salt

The title compound was prepared from(S)—N-(3-(4-(4-amino-2-fluorophenoxy)pyridin-3-yl)prop-2-ynyl)-2-(pyrrolidin-1-ylmethyl)pyrrolidine-1-carboxamide(36 mg, 0.057 mmol) and 0.3 M solution of 2-(4-fluorophenyl)acetylisocyanate in toluene (Compound D of Example 11, 0.37 mL, 0.11 mmol) inthe same manner as in Step D of Example 33. The product was purified bypreparative HPLC (Column B) and converted to its hydrochloride accordingto Step C of Example 43 to give the title compound (10 mg, 25%) as anamber colored oil. ¹H NMR (DMSO-d₆) δ 11.06 (s, 1H), 10.60 (s, 1H), 9.56(s, 1H), 8.58 (s, 1H), 8.38 (d, 1H, J=5.6 Hz), 7.80 (dd, 1H, J=2.6, 12.7Hz), 7.42 (dm, 1H, J=10.6 Hz), 7.38-7.31 (m, 2H), 7.30-7.25 (m, 1H),7.20-7.10 (m, 2H), 6.69 (d, 1H, J=6.1 Hz), 4.26-4.12 (m, 2H), 3.79-3.69(m, 3H), 3.56 (s, 2H), 3.31-3.18 (m, 2H), 3.17-2.93 (m, 2H), 2.14-2.02(m, 4H), 2.03-1.76 (m, 5H), 1.71-1.61 (m, 1H); MS (ESI⁺): m/z 617.20(M+H)⁺.

Example 45

(E)-1-(4-(3-(3-(4-Aminopiperidin-1-yl)-3-oxoprop-1-enyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,ditrifluoroacetic acid salt

A) (E)-tert-Butyl 3-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)acrylate

A mixture of 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridine (Compound A ofExample 33, 150 mg, 0.42 mmol), tert-butylacrylate (Aldrich, 107 mg,0.84 mmol), tri-n-butylamine (0.21 mL, 0.92 mmol) and DMF (2 mL) wasdegassed by vacuum/argon purge and then treated with Pd(OAc)₂ (17 mg,0.078 mmol). The mixture was heated at 100-130° C. for under argon for45 min, then the mixture was cooled to rt, partitioned between EtOAc andsaturated aq. NaHCO₃ solution. The phases were separated and the EtOAcextracts were washed with saturated aq. NaHCO₃ solution and brine, dried(MgSO₄) and concentrated in vacuo. The crude product was purified byflash chromatography on SiO₂ eluting with 0-20% EtOAc/CH₂Cl₂ to give thetitle compound (118 mg, 78%) as a pale yellow oil which solidified atroom temperature. ¹H NMR (DMSO-d₆) δ 9.02 (s, 1H), 8.49 (d, 1H, J=5.5Hz), 8.46 (dd, 1H, J=2.5, 11.7 Hz), 8.21 (dm, 1H, J=9.2 Hz), 7.74 (d,1H, J=16.3 Hz), 7.65 (dd, 1H, J=8.1, 8.6 Hz), 6.95 (d, 1H, J=6.1 Hz),6.77 (d, 1H, J=16.3 Hz), 1.47 (s, 9H); MS (ESI⁺): m/z 361.15 (M+H)⁺.

B) (E)-3-(4-(2-Fluoro-4-nitrophenoxy)pyridin-3-yl)acrylic acid

(E)-tert-Butyl 3-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)acrylate (115mg, 0.32 mmol) was treated with 1:1 TFA/CH₂Cl₂ (6 mL) and stirred atroom temperature for 1.5 h. The mixture was concentrated under vacuumand the residue treated with MeOH (5 mL) and 2 M HCl/Et₂O (15 mL) andconcentrated under vacuum. A second treatment with MeOH (5 mL) and 2 MHCl/Et₂O (15 mL) and reconcentration gave the title compound (120 mg).¹H NMR (DMSO-d₆) δ 9.17 (s, 1H), 8.62 (d, 1H, J=6.6 Hz), 8.50 (dd, 1H,J=2.6, 10.1 Hz), 8.25 (d, 1H, J=9.1 Hz), 7.78 (d, 1H, J=16.3 Hz), 7.74(dd, 1H, J=8.1, 8.6 Hz), 7.17 (d, 1H, J=6.1 Hz), 6.87 (d, 1H, J=16.3Hz); MS (ESI⁺): m/z 305.11 (M+H)⁺.

C) (E)-tert-Butyl1-(3-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)acryloyl)piperidin-4-ylcarbamate

A solution of (E)-3-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)acrylicacid (143 mg, 0.42 mmol), 4-N-Boc-aminopiperidine (Aldrich, 84 mg, 0.42mmol) in DMF (1.5 mL) was treated with DIPEA (160 μL, 0.92 mmol), andTBTU (160 mg, 0.50 mmol) and the mixture stirred at rt for 2 h. Themixture was diluted with EtOAc, washed with saturated aq. NaHCO₃solution and brine, dried (MgSO₄) and concentrated in vacuo. The crudeproduct was purified by flash chromatography on silica gel eluting firstwith 30-100% EtOAc/hexanes then 5% MeOH/CH₂Cl₂ to give the titlecompound (110 mg, 54%) as a light brown solid. ¹H NMR (DMSO-d₆) δ 9.15(s, 1H), 8.48 (d, 1H, J=5.6 Hz), 8.44 (dd, 1H, J=2.5, 10.5 Hz), 8.18 (d,1H, J=9.2 Hz), 7.69 (d, 1H, J=15.3 Hz), 7.58 (dd, 1H, J=8.6, 8.6 Hz),7.50 (d, 1H, J=15.7 Hz), 6.97 (d, 1H, J=5.6 Hz), 6.89 (d, 1H, J=7.6 Hz),4.31-4.16 (m, 2H), 3.55-3.46 (m, 1H), 3.20-3.14 (m, 1H), 2.83-2.81 (m,1H), 1.82-1.71 (m, 2H), 1.34-1.18 (m, 2H), 1.37 (s, 9H); MS (ESI⁺): m/z431.04 (100) [(M-C₄H₉)⁺H]⁺; m/z 487.10 (90) (M+H)⁺.

D) (E)-tert-Butyl1-(3-(4-(4-amino-2-fluorophenoxy)pyridin-3-yl)acryloyl)piperidin-4-ylcarbamate

The title compound was prepared by the reduction of (E)-tert-butyl1-(3-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)acryloyl)piperidin-4-ylcarbamate(100 mg, 0.21 mmol) in a manner similar to that of Step E of Example 35using Fe powder (55 mg, 2.7 mmol), NH₄Cl (280 mg, 5.3 mmol). The product(90 mg, 95%) was obtained as a light brown solid which was used directlyin the subsequent step. MS (ESI⁺): m/z 457.18 (M+H)⁺.

E) (E)-tert-Butyl1-(3-(4-(2-fluoro-4-(3-(2-(4-fluorophenyl)acetyl)ureido)phenoxy)pyridin-3-yl)acryloyl)piperidin-4-ylcarbamate

The title compound was prepared from (E)-tert-butyl1-(3-(4-(4-amino-2-fluorophenoxy)pyridin-3-yl)acryloyl)piperidin-4-ylcarbamate(42 mg, 0.092 mmol) and 0.3 M solution of 2-(4-fluorophenyl)acetylisocyanate in toluene (Compound D of Example 11, 0.50 mL, 0.15 mmol) ina manner similar to that of Step D of Example 33. The crude product wasadsorbed onto silica gel and purified by flash chromatography elutingwith 0-5% MeOH/EtOAc to give the product (20 mg, 33%) as a white solid.¹H NMR (DMSO-d₆) δ 11.05 (s, 1H), 10.59 (s, 1H), 9.03 (s, 1H), 8.37 (d,1H, J=5.6 Hz), 7.82-7.74 (m, 2H), 7.47 (d, 1H, J=15.8 Hz), 7.42-7.33 (m,4H), 7.20-7.13 (m, 2H), 6.89 (d, 1H, J=8.1 Hz), 6.63 (d, 1H, J=5.6 Hz),4.31 (d, 1H, J=13.7 Hz), 4.19 (d, 1H, J=12.7 Hz), 3.74 (s, 2H),3.56-3.47 (m, 1H), 3.22-3.13 (m, 1H), 2.84-2.76 (m, 1H), 1.76 (s, 2H),1.37 (s, 9H), 1.32-1.20 (m, 2H); MS (ESI⁺): m/z 636.23 (M+H)⁺.

F)(E)-1-(4-(3-(3-(4-Aminopiperidin-1-yl)-3-oxoprop-1-enyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,ditrifluoroacetic acid salt

(E)-tert-Butyl1-(3-(4-(2-fluoro-4-(3-(2-(4-fluorophenyl)acetyl)ureido)phenoxy)pyridin-3-yl)acryloyl)piperidin-4-ylcarbamate(15 mg, 0.024 mmol) was dissolved in anhydrous MeOH (0.5 mL), treatedwith 4 M HCl/1,4-dioxane (1.5 mL) and stirred at rt for 1 h. The mixturewas concentrated under vacuum to give the crude product which waspurified by preparative HPLC (Column A). The fraction containing theproduct was treated with excess 1 M hydrochloric acid, concentrated andlyophilized to give the title compound (8 mg, 44%) as a pale yellowsolid. ¹H NMR (DMSO-d₆) δ 11.07 (s, 1H), 10.61 (s, 1H), 9.10 (s, 1H),8.44 (s, 1H), 7.91 (m, 3H), 7.86-7.69 (m, 2H), 7.55-7.28 (m, 5H),7.23-7.08 (m, 2H), 6.80-6.72 (m, 1H), 5.61-5.33 (m, 1H), 4.45-4.20 (m,2H), 3.74 (s, 2H), 3.39-3.07 (m, 2H), 2.82-2.68 (m, 1H), 1.91-1.51 (m,2H), 1.50-1.15 (m, 1H); MS (ESI⁺): m/z 536.16 (M+H)⁺.

Example 46

1-(3-Fluoro-4-(3-(2-(pyridin-2-yl)ethynyl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea,dihydrochloride salt

A) 2-(2-(4-(2-Fluoro-4-nitrophenoxy)pyridin-3-yl)ethynyl)pyridine

A mixture of 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridine (Compound A ofExample 33, 50 mg, 0.14 mmol) and 2-ethynylpyridine (Aldrich, 57 mg,0.54 mmol), THF (1 mL) and Et₃N (1 mL) was degassed by vacuum/argonpurge and treated in turn with CuI (3 mg, 0.016 mmol) and (Ph₃P)₄Pd (10mg, 0.009 mmol). The mixture was heated at 60° C. 45 minutes, cooled,partitioned between EtOAc and saturated sodium bicarbonate and the EtOAcphase dried (MgSO₄) and concentrated in vacuo to give the crude product.Purification of the residue by flash column chromatography on SiO₂eluting with 0-1.5% MeOH/CH₂Cl₂ gave the title compound (42 mg, 89%) asa brown solid. ¹H NMR (DMSO-d₆) δ 8.91 (s, 1H), 8.60 (d, 1H, J=4.5 Hz),8.45 (dd, 1H, J=2.6, 10.7 Hz), 8.19 (d, 1H, J=9.1 Hz), 7.86-7.83 (m,1H), 7.66 (dd, 1H, J=8.7, 8.7 Hz), 7.57 (d, 1H, J=7.6 Hz), 7.45-7.42 (m,2H), 7.14 (d, 1H, J=4.5 Hz); MS (ESI⁺): m/z 336.20 (M+H)⁺.

B) 3-Fluoro-4-(3-(2-(pyridin-2-yl)ethynyl)pyridin-4-yloxy)benzenamine

The title compound was prepared from2-(2-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)ethynyl)pyridine (30 mg,0.090 mmol) in a manner similar to that of Step E of Example 35 to givethe title compound (20 mg) as a brown solid. MS (ESI⁺): m/z 306.20(M+H)⁺.

C)1-(3-Fluoro-4-(3-(2-(pyridin-2-yl)ethynyl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea,dihydrochloride salt

The title compound was prepared from3-fluoro-4-(3-(2-(pyridin-2-yl)ethynyl)pyridin-4-yloxy)benzenamine (19mg, 0.062 mmol) and 0.3 M solution of 2-(4-fluorophenyl)acetylisocyanate in toluene (Compound D of Example 11, 0.50 mL, 0.15 mmol) ina manner similar to that of Step D of Example 33. Purification of thereaction mixture by flash chromatography on SiO₂ eluting with 0-100%EtOAc/CH₂Cl₂ gave a white solid which was converted to the hydrochloridein a manner similar to Step D of Example 33 to give the title compound(19 mg, 60%) as a white solid. ¹H NMR (DMSO-d₆) δ 11.07 (s, 1H), 10.61(s, 1H), 8.79 (s, 1H), 8.63 (d, 1H, J=5.6 Hz), 8.47 (d, 1H, J=5.6 Hz),7.89-7.86 (m, 1H), 7.83 (dd, 1H, J=1.5, 12.7 Hz), 7.67 (d, 1H, J=7.6Hz), 7.47-7.43 (m, 2H), 7.39-7.35 (m, 1H), 7.30-7.27 (m, 1H), 7.20-7.16(m, 2H), 7.14-7.10 (m, 1H), 6.77 (d, 1H, J=5.6 Hz), 3.75 (s, 2H); MS(ESI⁺): m/z 485.17 (M+H)⁺.

Example 47

1-(3-Fluoro-4-(3-(2-(pyridin-3-yl)ethynyl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea,dihydrochloride salt

A) 3-(2-(4-(2-Fluoro-4-nitrophenoxy)pyridin-3-yl)ethynyl)pyridine

A mixture of 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridine (Compound A ofExample 33, 50 mg, 0.14 mmol) and 3-ethynylpyridine (57 mg, 0.54 mmol),THF (1 mL) and Et₃N (1 mL) was degassed by vacuum/argon purge andtreated in turn with CuI (3 mg, 0.016 mmol), and (Ph₃P)₄Pd (10 mg, 0.009mmol). The mixture was heated at 60° C. 45 minutes, cooled, partitionedbetween EtOAc and saturated sodium bicarbonate and the EtOAc phase dried(MgSO₄) and concentrated in vacuo. Purification of the residue by flashchromatography on SiO₂ eluting with 0-1.5% MeOH/CH₂Cl₂ gave the titlecompound (33 mg, 77%) as a brown solid. ¹H NMR (DMSO-d₆) δ 8.86 (s, 1H),8.65 (s, 1H), 8.61-8.57 (m, 2H), 8.45 (dd, 1H, J=2.6, 10.7 Hz), 8.18 (d,1H, J=9.2 Hz), 7.90 (d, 1H, J=9.2 Hz), 7.62 (dd, 1H, J=8.7, 8.7 Hz),7.46 (dd, 1H, J=4.6, 8.1 Hz), 7.17 (d, 1H, J=5.6 Hz); MS (ESI⁺): m/z336.19 (M+H)⁺.

B) 3-Fluoro-4-(3-(2-(pyridin-3-yl)ethynyl)pyridin-4-yloxy)benzenamine

The title compound was prepared from3-(2-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)ethynyl)pyridine (30 mg,0.090 mmol) in a manner similar to Step E of Example 35 to give thetitle compound as a brown solid (25 mg, 93%). MS (ESI⁺): m/z 306.20(M+H)⁺.

C)1-(3-Fluoro-4-(3-(2-(pyridin-3-yl)ethynyl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea,dihydrochloride salt

The title compound was prepared from3-fluoro-4-(3-(2-(pyridin-3-yl)ethynyl)pyridin-4-yloxy)benzenamine (22mg, 0.072 mmol) and 0.3 M solution of 2-(4-fluorophenyl)acetylisocyanate in toluene (Compound D of Example 11, 0.50 mL, 0.15 mmol) ina manner similar to Step D of Example 33. Purification of the reactionmixture by flash column chromatography on SiO₂ eluting with 0-100%EtOAc/CH₂Cl₂ gave a white solid which was converted to the hydrochloridein a manner similar to Step D of Example 33 to give the title compound(15 mg, 38%) as a white solid. ¹H NMR (DMSO-d₆) δ 11.04 (s, 1H), 10.59(s, 1H), 8.76 (s, 1H), 8.74 (d, 1H, J=1.1 Hz), 8.60 (dd, 1H, J=5.6, 1.1Hz), 8.45 (d, 1H, J=6.1 Hz), 7.98 (d, 1H, J=7.7 Hz), 7.80 (d, 1H, J=12.1Hz), 7.47-7.45 (m, 1H), 7.41 (s, 2H), 7.36-7.34 (m, 2H), 7.16 (dd, 2H,J=8.8, 8.9 Hz), 6.78 (d, 1H, J=5.5 Hz), 3.74 (s, 2H); MS (ESI⁺): 485.13m/z.

Example 48

N-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-2-bromoisonicotinamide,trifluoroacetic acid salt

A) 2-Bromo-isonicotinicacyl chloride

A solution of 2-bromo-isonicotinic acid (Lancaster, 70 mg, 0.34 mmol) inthionyl chloride (1.2 mL) was heated at reflux temperature for 1.5 h.The mixture was concentrated and the crude product of2-bromoisonicotinoyl chloride was used directly in the next step withoutfurther purification.

B) N-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-2-bromoisonicotinamide

To the above residue was added a solution of4-(4-amino-2-fluorophenoxy)pyridine-2-amine (Compound B of Example 24,70 mg, 0.32 mmol) in CH₂Cl₂ (3 mL) at rt, and the reaction was stirredfor 1 h. The reaction mixture was concentrated and the residue waspurified by preparative HPLC to obtain the title compound (75 mg, 45%)as a yellow solid (TFA salt). ¹H NMR (DMSO-d₆) δ 11.03 (s, 1H), 8.62 (d,1H, J=5.0 Hz), 8.17 (s, 1H), 7.89-8.04 (m, 4H), 7.71 (d, 1H, J=8.8 Hz),7.51 (t, 1H, J=9.3 Hz), 6.72 (dd, 1H, J=7.1, 2.2 Hz), 6.18 (d, 1H, J=2.2Hz); MS (ESI⁺) m/z 403, 405 (M+H)⁺.

Example 49

N-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenylamino)isonicotinamide, bis-trifluoroacetic acid salt

A) 2-(4-Fluorophenylamino)isonicotinic acid

To a mixture of 2-fluoro-isonicotinic acid (Aldrich, 423 mg, 3.0 mmol)and 4-fluoroaniline (555 mg, 5.0 mmol) in DMF (18 mL) at rt was addedNaH (500 mg of 60% in oil), and the mixture was heated at 85° C. for 75min. Acetic acid (0.7 mL) was added to the reaction mixture and it wasconcentrated in vacuo. To the residue were added EtOAc (100 mL) andwater (20 mL), stirred for 20 min and the solid was filtered, washedwith EtOAc and dried to obtain the desired product (600 mg, 50%) as atan solid. ¹H NMR (DMSO-d₆) δ 8.98 (s, 1H), 8.43 (s, 1H), 8.04 (d, 1H,J=4.9 Hz), 7.69 (dd, 2H, J=8.8, 4.9 Hz), 7.24 (s, 1H), 7.05 (dd, 2H,J=8.2, 6.0 Hz); MS (ESI⁺) m/z 233.3 (M+H)⁺.

B) 2-(4-Fluorophenylamino)isonicotinicacyl chloride

A mixture of 2-(4-fluorophenylamino)isonicotinic acid (464 mg, 2.0 mmol)and thionyl chloride (10 mL) was heated at reflux temperature for 2 h.The reaction was concentrated in vacuo, and the crude product was useddirectly in the next step.

C)N-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenylamino)isonicotinamide

A solution of 4-(4-amino-2-fluorophenoxy)pyridine-2-amine (Compound B ofExample 24, 450 mg, 2.1 mmol) in 1,2-dichloroethane (10 mL) was addedslowly to a solution of acylchloride obtained above in1,2-dichloroethane (10 mL) at ice bath temperature with stirring. Thereaction mixture was allowed to stand at rt overnight. To the reactionmixture were added EtOAc (150 mL) and saturated aq. NaHCO₃ solution (50mL). The EtOAc layer was separated, dried over MgSO₄ and concentrated invacuo. The residue was purified by preparative HPLC to obtain the titlecompound (69 mg, 6.3%) as a yellow solid (bis-TFA salt). ¹H NMR(DMSO-d₆) δ 10.90 (s, 1H), 9.32 (s, 1H), 8.27 (d, 1H, J=5.5 Hz),7.92-7.07 (m, 11H), 6.68 (dd, 1H, J=7.1, 2.2 Hz), 6.10 (d, 1H, J=2.2Hz); MS (ESI⁺) m/z 217.9 (M+H)⁺.

Example 50

N-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-6-oxo-1,6-dihydropyridine-2-carboxamide,trifluoroacetic acid salt

To a solution of 6-hydroxypicolinic acid (Aldrich, 28 mg, 0.20 mmol) andHOBt (28 mg, 0.21 mmol) in DMF (2 mL) at rt was added EDCI.HCl (50 mg,0.26 mmol) followed by 4-(4-amino-2-fluorophenoxy)pyridine-2-amine(Compound B of Example 24, 42 mg, 0.19 mmol), and the reaction mixturewas stirred overnight at rt. Purification of the reaction mixture bypreparative HPLC afforded the desired product (24 mg, 25%) as a lightbrown solid (TFA salt). ¹H NMR (CD₃OD) δ 8.03 (dd, 1H, J=12.6, 2.2 Hz),7.79-7.36 (m, 5H), 6.85 (d, 1H, J=8.8 Hz), 6.67 (dd, 1H, J=7.2, 4.4 Hz),6.22 (d, 1H, J=2.2 Hz); MS (ESI⁺) m/z 341.3 (M+H)⁺.

Example 51

N-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide,trifluoroacetic acid salt

To a solution of 2-hydroxynicotinic acid (Aldrich, 42 mg, 0.30 mmol) andHOBt (18 mg) in DMF (2 mL) at rt was added EDCI.HCl (80 mg, 0.42 mmol)followed by 4-(4-amino-2-fluorophenoxy)pyridine-2-amine (Compound B ofExample 24, 65 mg, 0.30 mmol), and the reaction mixture was stirred for20 h at rt. Purification of the reaction mixture by preparative HPLCafforded the desired product (70 mg, 49%) as a beige-colored solid (TFAsalt). ¹H NMR (CD₃OD) δ 8.59 (dd, 1H, J=7.1, 2.2 Hz), 8.03 (dd, 1H,J=12.6, 2.2 Hz), 7.83 (d, 1H, J=7.7 Hz), 7.75 (dd, 1H, J=6.6, 2.2 Hz),7.44 (d, 1H, J=8.8 Hz), 7.32 (t, 1H, J=8.8 Hz), 6.67 (m, 2H), 6.21 (d,1H, J=2.2 Hz); MS (ESI⁺) m/z 341.2 (M+H)⁺.

Example 52

N-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide,trifluoroacetic acid salt

To a solution of 2-hydroxy-6-methylnicotinic acid (Lancaster, 72 mg,0.47 mmol) and HOBt (50 mg) in DMF (5 mL) at rt was added EDCI.HCl (130mg, 0.68 mmol) followed by 4-(4-amino-2-fluorophenoxy)pyridine-2-amine(Compound B of Example 24, 110 mg, 0.50 mmol), and the reaction mixturewas stirred at rt over 72 h. Purification of the reaction mixture bypreparative HPLC afforded the desired product (125 mg, 55%) as abeige-colored solid (TFA salt). ¹H NMR (CD₃OD) δ 8.46 (d, 1H, J=7.9 Hz),8.03 (dd, 1H, J=12.7, 2.8 Hz), 7.83 (d, 1H, J=7.1 Hz), 7.44 (dd, 1H,J=8.8, 2.2 Hz), 7.33 (t, 1H, J=8.8 Hz), 6.67 (dd, 1H, J=7.7, 2.7 Hz),6.45 (d, 1H, J=7.7 Hz), 6.21 (d, 1H, J=2.8 Hz), 2.40 (s, 3H); MS (ESI⁺)m/z 355.2 (M+H)⁺.

Example 53

N-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-5-chloro-2-oxo-1,2-dihydropyridine-3-carboxamide,trifluoroacetic acid salt

To a solution of 2-hydroxy-5-chloronicotinic acid (Avocado, 87 mg, 0.50mmol) and HOBt (40 mg) in DMF (4 mL) at rt was added EDCI.HCl (130 mg,0.68 mmol) followed by 4-(4-amino-2-fluorophenoxy)pyridine-2-amine(Compound B of Example 24, 110 mg, 0.50 mmol), and the reaction mixturewas stirred for 72 h. Purification of the reaction mixture bypreparative HPLC afforded the desired product (115 mg, 45%) as abeige-colored solid (TFA salt). ¹H NMR (CD₃OD) δ 8.50 (d, 1H, J=3.3 Hz),8.03 (dd, 1H, J=12.6, 2.1 Hz), 7.84 (m, 2H), 7.46 (d, 1H, J=8.8 Hz),7.34 (t, 1H, J=8.8 Hz), 6.67 (dd, 1H, J=7.2, 2.2 Hz), 6.21 (d, 1H, J=2.2Hz); MS (ESI⁺) m/z 375.1, 377.1 (M+H)⁺.

Example 54

N-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-5-bromo-2-oxo-1,2-dihydropyridine-3-carboxamide,trifluoroacetic acid salt

To a solution of 2-hydroxy-5-bromo-nicotinic acid (147 mg, 0.67 mmol,Syn. Comm., 1989, 19, 553-559) and HOBt (30 mg) in DMF (4 mL) at rt wasadded EDCI.HCl (160 mg, 0.83 mmol) followed by4-(4-amino-2-fluorophenoxy)pyridine-2-amine (Compound B of Example 24,147 mg, 0.67 mmol), and the reaction mixture was stirred at rtovernight. Purification of the reaction mixture by preparative HPLCafforded the title compound (120 mg, 33%) as a beige-colored solid (TFAsalt). ¹H NMR (DMSO-d₆) δ 13.22 (s, 1H), 12.23 (s, 1H), 8.40 (d, 1H,J=2.8 Hz), 8.14 (d, 1H, J=2.8 Hz), 8.12-7.46 (m, 5H), 6.68 (dd, 1H,J=7.2, 2.2 Hz), 6.14 (d, 1H, J=2.2 Hz); MS (ESI⁺) m/z 419/421 (M+H)⁺.

Example 55

N-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxamide,trifluoroacetic acid salt

To a solution of 4-hydroxy-6-methyl-nicotinic acid (Wako, 77 mg, 0.50mmol) and HOBt (50 mg) in DMF (5 mL) at rt was added EDCI.HCl (130 mg,0.68 mmol) followed by 4-(4-amino-2-fluorophenoxy)pyridine-2-amine(Compound B of Example 24, 110 mg, 0.50 mmol), and the reaction mixturewas stirred at rt overnight, and then heated at 75° C. for 1.5 h. Aftercooling the reaction mixture to rt purification by preparative HPLCafforded the title compound (70 mg, 29%) as a white solid (TFA salt). ¹HNMR (DMSO-d₆) δ 13.22 (br s, 1H), 12.53 (s, 1H), 8.47 (d, 1H, J=5.5 Hz),8.04 (d, 1H, J=2.2 Hz), 7.95 (d, 1H, J=8.2 Hz), 7.82 (s, 2H), 7.46-7.42(m, 2H), 6.70 (dd, 1H, J=7.7, 2.7 Hz), 6.39 (s, 1H), 6.14 (d, 1H, J=2.2Hz); MS (ESI⁺) m/z 355.3 (M+H)⁺.

Example 56

N-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-5-benzyl-4-oxo-1,4-dihydropyridine-3-carboxamide,trifluoroacetic acid salt

A) 3-Bromo-5-(hydroxy(phenyl)methyl)pyridin-4-ol

To a heterogeneous mixture of 3,5-dibromo-4-hydroxypyridine (2.53 g, 10mmol, prepared following the procedure in Synthesis, 2001, 14,2175-2179) in anhydrous THF (20 mL) at −78° C. under Ar-atm was addedphenylmagnesium bromide solution (11 mL of 1 M solution in THF, 11mmol). After stirring for 15 min. was added n-BuLi solution (5.5 mL of 2M solution in cyclohexane), and the reaction mixture was stirred for 15min at −78° C. under Ar-atm. To this mixture benzaldehyde (2.15 mL) wasadded and the reaction mixture was stirred for 2 h −78° C. under Ar-atm.The reaction mixture was quenched by adding HOAc (3 mL) and TFA (3 mL),concentrated in vacuo and the residue was purified by flash columnchromatography on silica gel eluting with hexane/EtOAc/MeOH/750:250:50followed by hexane/EtOAc/MeOH/Et₃N/460:460:50:10 to afford the desiredproduct (2.85 g, 91%) as a white solid. ¹H NMR (CD₃OD) δ 8.13 (s, 1H),8.04 (s, 1H), 7.41-7.20 (m, 5H), 5.94 (s, 1H); MS (ESI⁺) m/z 280, 282(M+H)⁺.

B) 3-Benzyl-5-bromopyridin-4-ol

A mixture of 3-bromo-5-(hydroxy(phenyl)methyl)pyridin-4-ol (2.55 g, 91mmol), TFA (16 mL) and Et₃SiH in CH₂Cl₂ (30 mL) was stirred at rt for 10h. The reaction mixture was concentrated in vacuo and the residue waspurified by flash column chromatography on silica gel eluting withhexane/EtOAc/MeOH/600:300:50 followed by hexane/EtOAc/MeOH/400:400:50:10to afford an impure product which was triturated with a small amount ofMeOH and Et₂O to obtain the desired product (255 mg, 10%) as a whitesolid. ¹H NMR (DMSO-d₆) δ 11.75 (br s, 1H), 8.13 (s, 1H), 7.54 (s, 1H),7.26-7.14 (m, 5H), 2.49 (s, 2H).

C) 5-Benzyl-4-hydroxynicotinic acid

To a solution of 3-benzyl-5-bromopyridin-4-ol (220 mg, 0.83 mmol) inanhydrous THF (8 mL) at −78° C. under Ar-atm was added MeLi solution(0.61 mL of 1.5 M solution in THF, 0.92 mmol). After stirring for 5 min.n-BuLi solution (0.5 mL of 2 M solution in cyclohexane, 1.0 mmol) wasadded and the mixture was stirred for 15 min at −78° C. under Ar-atm.Carbon dioxide was bubbled through the reaction mixture for 20 min at−78° C. The reaction mixture was then quenched by adding HOAc (2 mL),concentrated in vacuo and the residue was purified by preparative HPLCto afford the desired product (100 mg, 35%) as a white solid (TFA salt).¹H NMR (DMF-d₇) δ 12.99 (br s, 1H), 8.69 (s, 1H), 8.28 (s, 1H),7.35-7.19 (m, 5H), 3.90 (s, 2H); MS (ESI⁺) m/z 230.1 (M+H)⁺.

D)N-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-5-benzyl-4-oxo-1,4-dihydropyridine-3-carboxamide,trifluoroacetic acid salt

To a solution of 4-hydroxy-5-benzylnicotinic acid (35 mg, 0.15 mmol) andHOBt (30 mg) in DMF (2.5 mL) at rt was added EDCI.HCl (80 mg, 0.42 mmol)followed by 4-(4-amino-2-fluorophenoxy)pyridine-2-amine (Compound B ofExample 24, 35 mg, 0.16 mmol), and the reaction mixture was stirred for40 h at rt. Purification of the reaction mixture by preparative HPLCafforded the desired product (35 mg, 43%) as a white TFA solid salt. ¹HNMR (DMSO-d₆) δ 13.25 (br s, 1H), 12.44 (s, 1H), 8.59 (d, 1H, J=4.9 Hz),8.08 (dd, 1H, J=13.2, 2.2 Hz), 7.97 (d, 1H, J=7.1 Hz), 7.81 (d, 1H,J=9.4 Hz), 7.52-7.19 (m, 7H), 6.72 (dd, 1H, J=7.2, 2.2 Hz), 6.15 (d, 1H,J=2.5 Hz), 3.81 (s, 2H), 3.51 (br s, 2H); MS (ESI⁺) m/z 431.2 (M+H)⁺.

Example 57

N-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide,trifluoroacetic acid salt

A) (E)-Dimethyl 2-(3-(phenylamino)allylidene)malonate

To a solution of 2-(3-methoxyallylidene)malonic acid dimethyl ester(Acros Organics, 200 mg, 1.0 mmol) in THF (2 mL) at rt was added aniline(300 mg, 3.2 mmol) and the reaction mixture was heated at 60° C. for 8.5h. Purification of the reaction mixture by preparative HPLC provided thedesired product (150 mg, 57%) as a yellow solid. ¹H NMR (DMSO-d₆) δ10.16 (d, 1H, J=12.7 Hz), 8.06 (t, 1H, J=12.7 Hz), 7.74 (d, 1H, J=12.7Hz), 7.30 (t, 2H, J=8.7 Hz), 7.16 (d, 2H, J=7.7 Hz), 6.98 (t, 1H, J=7.7Hz), 6.35 (t, 1H, J=12.1 Hz), 3.69 (s, 3H), 3.65 (s, 3H).

B) Methyl 2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylate

To a solution of the aniline adduct obtained above (130 mg, 0.50 mmol)in methanol (8 mL) at rt was added NaH (50 mg of the 60% NaH in oil, 1.2mmol) and the mixture was stirred at rt for 3 h. Acetic acid (0.3 mL)was added to the mixture, concentrated to a volume of ˜4 mL, andpurification of the reaction mixture by preparative HPLC provided thedesired product (105 mg, 92%) as a yellow solid. ¹H NMR (CD₃OD) δ 8.30(dd, 1H, J=7.2, 2.2 Hz), 7.87 (dd, 1H, J=6.6, 1.7 Hz), 7.57-7.38 (m,5H), 6.53 (t, 1H, J=7.0 Hz), 3.84 (s, 3H); MS (ESI⁺) m/z 230.3 (M+H)⁺.

C) 2-Oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid

A mixture of methyl 2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylate (70mg, 0.31 mmol) and LiOH (40 mg) in methanol (6 mL) and water (1 mL) wasstirred at rt overnight. To the reaction mixture were added EtOAc (50mL) and 1 N aq HCl (15 mL). The EtOAc layer was separated, dried overMgSO₄, and concentrated in vacuo to afford the product (55 mg, 83%) as alight yellow solid. ¹H NMR (DMF-d₇) δ 11.77 (br s, 1H), 8.57 (dd, 1H,J=7.4, 2.0 Hz), 8.26 (dd, 1H, J=6.6, 1.6 Hz), 7.64-7.55 (m, 5H), 6.88(t, 1H, J=7.0 Hz); MS (ESI⁺) m/z 216.2 (M+H)⁺.

D)N-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

To a solution of 2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid(36 mg, 0.17 mmol) and HOBt (18 mg) in DMF (3 mL) at rt was addedEDCI.HCl (45 mg, 0.23 mmol) followed by4-(4-amino-2-fluorophenoxy)pyridine-2-amine (Compound B of Example 24,36 mg, 0.17 mmol), and the reaction mixture was stirred at rt overnight.Purification of the reaction mixture by preparative HPLC afforded thetitle compound (32 mg, 36%) as a beige colored solid (TFA salt). ¹H NMR(DMSO-d₆) δ 13.35 (br s, 1H), 12.11 (s, 1H), 8.52 (dd, 1H, J=7.3, 2.1Hz), 8.08 (dd, 1H, J=6.6, 2.1 Hz), 8.03 (d, 1H, J=2.3 Hz), 7.89 (d, 1H,J=7.2 Hz), 7.81 (s, 1H), 7.54-7.36 (m, 6H), 6.69-6.63 (m, 2H), 6.08 (d,1H, J=2.4 Hz), 3.55 (br s, 1H); MS (ESI⁺) m/z 417.2 (M+H)⁺.

Example 58

N-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-6-(4-fluorophenyl)pyridyl-N-oxide-amide,trifluoroacetic acid salt

A) 6-(4-Fluorophenyl)picolinic acid

A solution of 2-bromo-picolinic acid (Aldrich, 2.02 g, 10 mmol) in DMEcontaining 4 mL of 10% aq Na₂CO₃ was purged with Ar gas. To this mixturewas added Pd(PPh₃)₄ followed by2-(4-fluorophenyl)-5,5-dimethyl-1,3,2-dioxaborinane (Aldrich, 2.40 g,11.5 mmol) and EtOH (20 mL), and the mixture was purged with Ar gas. Thereaction mixture was heated at 100° C. for 2.5 h in a sealed tube.Additional 2-bromo-picolinic acid (900 mg) and Pd(PPh₃)₄ was added, andafter purging with Ar gas it was heated at 100° C. for 4.5 h.Trifluoroacetic acid (20 mL) was added to the reaction and the mixturewas concentrated in vacuo. MeOH (150 mL) was added to the residue andthe insoluble material was filtered, and the filtrate solution wasconcentrated in vacuo. Purification of the resulting residue by flashcolumn chromatography on silica gel eluting with EtOAc/MeOH/900:100followed by EtOAc/MeOH/HOAc/700:1500:50 provided the desired product(1.0 g, 40% based on borinane starting material) as a white solid. ¹HNMR (CD₃OD) δ 8.01 (d, 1H, J=7.7 Hz), 7.94-7.87 (m, 3H), 7.73 (d, 1H,J=7.7 Hz), 7.13 (t, 2H, J=8.8 Hz); MS (ESI⁺) m/z 234 (M+H)⁺.

B) 6-(4-Fluorophenyl)picolinic acid-N-oxide

A mixture of picolinic acid derivative (1.0 g, 4.6 mmol), Na₂HPO₄ (1.2g) and m-CPBA (1.1 g, ˜70% from Aldrich) in CH₂ClCH₂Cl (30 mL) wasstirred at rt for 2 h. Additional Na₂HPO₄ (0.8 g) and m-CPBA (1.0 g) wasadded to the reaction mixture and it was stirred for 3 h at rt. AnotherNa₂HPO₄ (0.5 g) and m-CPBA (0.5 g) was added to the reaction mixture andit was stirred at rt overnight. CHCl₃ (160 mL) and 2 N aq. HCl solution(50 mL) were added to the reaction mixture and the organic layer wasseparated, dried over MgSO₄ and concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel eluting withEtOAc/MeOH/HOAc/700:240:60 to obtain the desired product which wascontaminated with m-CPBA. This impure material was purified bypreparative HPLC to obtain the desired product (175 mg, 16%) as a whitesolid. ¹H NMR (DMF-d₇) 8.45 (dd, 1H, J=8.3, 2.2 Hz), 8.15 (d, 1H, J=2.2Hz), 8.13-8.00 (m, 4H), 7.45 (t, 2H, J=8.7 Hz).

C)N-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-6-(4-fluorophenyl)pyridyl-N-oxide-amide,trifluoroaacetic acid salt

To a solution of 6-(4-fluorophenyl)picolinic acid-N-oxide (23 mg, 0.1mmol) and HOBt (10 mg) in DMF (2 mL) at rt was added EDCI.HCl (30 mg,0.16 mmol) followed by 4-(4-amino-2-fluorophenoxy)pyridine-2-amine(Compound B of Example 24, 22 mg, 0.1 mmol), and the reaction mixturewas stirred at rt overnight. Purification of the reaction mixture bypreparative HPLC afforded the title compound (25 mg, 46%) as a whitesolid (TFA salt). ¹H NMR (DMF-d₇) δ 14.00 (s, 1H), 8.43 (dd, 1H, J=8.0,2.2 Hz), 8.15 (dd, 1H, J=12.8, 2.4 Hz), 8.08 (d, 1H, J=7.1 Hz),7.99-7.37 (m, 9H), 6.72 (dd, 1H, J=7.0, 2.4 Hz), 6.32 (d, 1H, J=2.3 Hz),3.7 (br s, 2H); MS (ESI⁺) m/z 417.2 (M+H)⁺.

Example 59

1-(4-(3-(4-(2-Amino-2-oxoethyl)phenyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,hydrochloride salt

A) 2-(4-(4-(2-Fluoro-4-nitrophenoxy)pyridin-3-yl)phenyl)acetic acid

A 25 mL round bottom flask was charged with4-(2-fluoro-4-nitrophenoxy)-3-iodopyridine (Compound A of Example 33,120 mg, 0.33 mmol),2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid(Frontier Scientific, 131 mg, 0.50 mmol),tetrakis(triphenylphosphine)palladium(0) (Strem Chemicals, 38 mg, 0.033mmol), and sodium carbonate (245 mg, 2.3 mmol). The flask was flushedwith nitrogen and then charged with dioxane and water (1 mL each). Afterstirring at 80° C. for 10 h, the mixture was cooled to room temperatureand then concentrated in vacuo. The crude product was purified by flashcolumn chromatography on silica gel (30% MeOH/EtOAc) to give the titlecompound (120 mg, 99%) as a white solid. ¹H NMR (CD₃OD) δ 8.61 (s, 1H),8.48 (d, 1H, J=5.6 Hz), 8.22 (dd, 1H, J=10.4, 2.8 Hz), 8.14-8.11 (m,1H), 7.54 (d, 2H, J=8.1 Hz), 7.41 (d, 2H, J=8.0 Hz), 7.40 (m, 1H), 7.05(d, 1H, J=5.7 Hz), 3.56 (s, 2H); MS (ESI⁺) m/z 369.16 (M+H)⁺.

B) 2-(4-(4-(2-Fluoro-4-nitrophenoxy)pyridin-3-yl)phenyl)acetamide

A 25 mL round bottom flask was charged with2-(4-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)phenyl)acetic acid (50 mg,0.136 mmol), HOBT (46 mg, 0.34 mmol), and EDCI (65 mg, 0.34 mmol). Theflask was flushed with nitrogen and then DMF was added (1 mL). Afterstirring at rt for 1 h, the solution was cooled to 0° C. and thencharged with ammonium hydroxide (0.5 mL). The reaction was stirred at 0°C. for 1 h and was then diluted with brine (5 mL) and extracted withethyl acetate (3×5 mL). The combined organic extracts were dried overanhydrous Na₂SO₄ and concentrated in vacuo. The crude product waspurified by flash column chromatography on silica gel (20% MeOH/EtOAc)to give the title compound (33 mg, 66%) as a colorless oil. ¹H NMR(CD₃OD) δ 8.49 (s, 1H), 8.38 (d, 1H, J=5.6 Hz), 8.10 (dd, 1H, J=10.4,2.4 Hz), 7.99 (m, 1H), 7.45 (d, 2H, J=8.2 Hz), 7.30 (d, 2H, J=8.2 Hz),7.28 (m, 1H), 6.93 (d, 1H, J=5.6 Hz), 3.44 (s, 2H); MS (ESI⁺) m/z 368.18(M+H)⁺.

C)1-(4-(3-(4-(2-Amino-2-oxoethyl)phenyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea

A solution of2-(4-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)phenyl)acetamide (33 mg,0.09 mmol) in THF (0.8 mL) and methanol (1.2 mL) was treated with Zndust (59 mg, 0.9 mmol) followed by ammonium chloride (48 mg, 0.9 mmol).The mixture was stirred at rt for 4 h and was then filtered through athin pad of Celite® with methanol. The filtrate was concentrated and theresidue partitioned between EtOAc and saturated aqueous sodiumbicarbonate solution. The EtOAc phase was dried over anhydrous Na₂SO₄and concentrated in vacuo to give the crude product (25 mg, 82%) as ayellow oil which was sufficiently pure to use in the next step withoutfurther purification. ¹H NMR (CD₃OD) δ 8.33 (s, 1H), 8.19 (d, 1H, J=5.6Hz), 7.49 (d, 2H, J=8.1 Hz), 7.32 (d, 2H, J=8.2 Hz), 6.82 (t, 1H, J=8.8Hz), 6.61 (d, 1H, J=5.6 Hz), 6.44 (qd, 1H, J=12.8, 2.8 Hz), 3.48 (s,2H); MS (ESI⁺) m/z 338.25 (M+H)⁺.

The above amine was dissolved in THF (1 mL) and then charged with2-(4-fluorophenyl)acetyl isocyanate (Compound D of Example 11, 250 uL,0.074 mmol, 0.3 M in toluene). After stirring at rt for 1 h, thereaction was purified directly by flash chromatography on silica gel(10% MeOH/EtOAc) to give the title compound as a white solid. The solidwas dissolved in dioxane (2 mL) and cooled to 0° C. Anhydrous HCl (2 mL,1 N in ether) was added. After stirring at 0° C. for 5 min, the solutionwas concentrated in vacuo. The resulting HCl salt was lyophilized fromacetonitrile/water to give the title compound (23 mg, 57%) as a whitesolid. ¹H NMR (DMSO-d₆) δ 11.02 (s, 1H), 10.59 (s, 1H), 8.83 (s, 1H),8.58 (d, 1H, J=6.4 Hz), 7.79 (dd, 1H, J=12.8, 2.4 Hz), 7.60 (d, 2H,J=8.4 Hz), 7.46-7.34 (m, 4H), 7.31-7.28 (m, 2H), 7.11 (t, 2H, J=8.7 Hz),6.88 (d, 1H, J=5.6 Hz), 3.70 (s, 2H), 3.40 (s, 2H); MS (ESI⁺) m/z 517.19(M+H)⁺.

Example 60

1-(4-(3-(4-(Aminomethyl)phenyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,trifluoroacetic acid salt

A) 4-(4-(2-Fluoro-4-nitrophenoxy)pyridin-3-yl)benzaldehyde

Prepared in a similar manner as Step A of Example 59 to give the titlecompound (86%) as a colorless oil. ¹H NMR (CD₃OD) δ 9.92 (s, 1H), 8.56(s, 1H), 8.41 (d, 1H, J=6 Hz), 8.12 (dd, 1H, J=10.3, 2.6 Hz), 8.05-8.01(m, 1H), 7.90 (d, 2H, J=8.3 Hz), 7.73 (d, 2H, J=8.2 Hz), 7.35 (t, 1H,J=8.4 Hz), 6.95 (d, 1H, J=6 Hz); MS (ESI⁺) m/z 339.19 (M+H)⁺.

B) tert-Butyl 4-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)benzylcarbamate

To 4-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)benzaldehyde (81 mg, 0.24mmol) in methanol (2 mL) was added ammonium acetate (185 mg, 2.4 mmol)followed by sodium cyanoborohydride (16 mg, 0.24 mmol). The reaction wasstirred at rt for 4 h and was then concentrated in vacuo. The residuewas dissolved in water (5 mL) and extracted with EtOAc (2×5 mL). Thecombined organic extracts were washed with saturated aqueous sodiumbicarbonate solution, dried over anhydrous Na₂SO₄, and concentrated invacuo. The crude product was dissolved in dichloromethane (2 mL) andthen triethylamine (50 uL, 0.36 mmol), DMAP (spatula tip), anddi-tert-butyl dicarbonate (Aldrich, 57 mg, 0.26 mmol) were addedsequentially. The reaction was stirred at rt for 2 h and was thenpurified directly by flash column chromatography on silica gel (EtOAc)to give the title compound (13 mg, 12%) as a colorless oil. ¹H NMR(CD₃OD) δ 8.50 (s, 1H), 8.37 (d, 1H, J=5.6 Hz), 8.09 (dd, 1H, J=6.1, 2.6Hz), 8.01-7.99 (m, 1H), 7.45 (d, 2H, J=8 Hz), 7.26 (d, 2H, J=8.2 Hz),7.25 (m, 1H), 6.95 (d, 1H, J=5.6 Hz), 4.16 (s, 2H), 1.35 (s, 9H); MS(ESI⁺) m/z 440.19 (M+H)⁺.

C)1-(4-(3-(4-(Aminomethyl)phenyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea

Prepared in a similar manner as Step C of Example 59. After acylureaformation, 4 N HCl in dioxane (5 mL) was added. After stirring at rt for5 min, the reaction was concentrated in vacuo. The residue was suspendedin EtOAc, washed with saturated aqueous sodium bicarbonate solution,dried over anhydrous Na₂SO₄, and concentrated in vacuo. The crudematerial was purified by prep HPLC. The appropriate fractions wereconcentrated in vacuo to remove methanol. Toluene was added and thenconcentrated (2×5 mL). The resulting solid was lyophilized fromacetonitrile/water to give the TFA salt of the title compound (6 mg,25%) as a white solid. ¹H NMR (DMSO-d₆) δ 11.00 (s, 1H), 10.53 (s, 1H),8.55 (s, 1H), 8.40 (d, 1H, J=4 Hz), 7.73 (dd, 1H, J=12, 4 Hz), 7.67 (d,2H, J=8 Hz), 7.51 (d, 2H, J=8 Hz), 7.34-7.27 (m, 4H), 7.13-7.09 (m, 2H),6.73 (d, 1H, J=4 Hz), 4.03 (s, 2H), 3.68 (s, 2H); MS (ESI⁺) m/z 489.18(M+H)⁺.

Example 61

1-(3-Fluoro-4-(3-(6-(piperazin-1-yl)pyridin-3-yl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea,hydrochloride salt

A) tert-Butyl4-(5-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)pyridin-2-yl)piperazine-1-carboxylate

Prepared in a similar manner as Step A of Example 59 to give the titlecompound (87%) as a colorless oil. ¹H NMR (CD₃OD) δ 8.62 (s, 1H), 8.46(d, 1H, J=6 Hz), 8.36 (d, 1H, J=2.4 Hz), 8.24 (dd, 1H, J=10.4, 2.8 Hz),8.15-8.11 (m, 1H), 7.84 (dd, 1H, J=8.8, 2.4 Hz), 7.41 (t, 1H, J=8.4 Hz),7.04 (d, 1H, J=5.6 Hz), 6.92 (d, 1H, J=8.8 Hz), 3.61-3.59 (m, 4H),3.56-3.54 (m, 4H), 1.50 (s, 9H); MS (ESI⁺) m/z 496.23 (M+H)⁺.

B) tert-Butyl4-(5-(4-(4-amino-2-fluorophenoxy)pyridin-3-yl)pyridin-2-yl)piperazine-1-carboxylate

Prepared in a similar manner as Step C of Example 59 to give the titlecompound (96%) as a colorless oil. ¹H NMR (CD₃OD) δ 8.34 (s, 1H), 8.29(d, 1H, J=2 Hz), 8.18 (d, 1H, J=6 Hz), 7.78 (dd, 1H, J=9.2, 2.8 Hz),6.87-6.83 (m, 2H), 6.61 (d, 1H, J=5.6 Hz), 6.48 (dd, 1H, J=12.8, 2.8Hz), 6.44-6.41 (m, 1H), 3.50-3.46 (m, 8H), 1.38 (s, 9H); MS (ESI⁺) m/z466.25 (M+H)⁺.

C)1-(3-Fluoro-4-(3-(6-(piperazin-1-yl)pyridin-3-yl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea

Prepared in a similar manner as Step C of Example 59 to give the titlecompound (28%) as the HCl salt. ¹H NMR (DMSO-d₆) δ 11.33 (s, 1H), 10.76(s, 1H), 9.09 (s, 1H), 8.74 (d, 1H, J=6.8 Hz), 8.57 (d, 1H, J=2.4 Hz),8.16 (dd, 1H, J=8.8, 2 Hz), 7.91 (dd, 1H, J=12.8, 2 Hz), 7.61 (t, 1H,J=8.8 Hz), 7.55-7.50 (m, 1H), 7.42-7.38 (m, 2H), 7.28 (d, 1H, J=6.5 Hz),7.27-7.18 (m, 3H), 3.98 (m, 4H), 3.82 (s, 2H), 3.23 (m, 4H); MS (ESI⁺)m/z 545.19 (M+H)⁺.

Example 62

N-(3-Fluoro-4-(3-(6-(piperazin-1-yl)pyridin-3-yl)pyridin-4-yloxy)phenyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide,hydrochloride salt

To tert-butyl4-(5-(4-(4-amino-2-fluorophenoxy)pyridin-3-yl)pyridin-2-yl)piperazine-1-carboxylate(Compound B of Example 61, 32 mg, 0.069 mmol) in THF/DMF (1 mL each) wasadded 2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid (Compound Cof Example 57, 15 mg, 0.069 mmol), DIPEA (60 uL, 0.35 mmol), then TBTU(Fluka, 33 mg, 0.10 mmol). After stirring at rt for 18 h, the reactionwas diluted with EtOAc (5 mL), washed with 10% aqueous lithium chloridesolution (2×5 mL) followed by saturated sodium bicarbonate solution (1×5mL), dried over anhydrous Na₂SO₄, and concentrated in vacuo. The residuewas suspended in ether, cooled to 0° C., and treated with 4 N HCl indioxane (5 mL). The solution was allowed to warm to rt and then stirredat rt for 2 h. The solution was concentrated in vacuo and the resultingcrude product was purified by prep HPLC. The appropriate fractions wereconcentrated to remove methanol and then made basic with saturatedaqueous sodium bicarbonate solution. The aqueous solution was extractedwith EtOAc (2×10 mL) and the pooled organic extracts were dried overanhydrous Na₂SO₄ and then concentrated in vacuo. The residue wasdissolved in THF (2 mL), cooled to 0° C., and treated with 1N HCl inether (0.5 mL). After stirring at 0° C. for 5 min, the mixture wasconcentrated. The resulting white solid was lyophilized fromacetonitrile/water to give the HCl salt of the title compound (26 mg,56%) as a pale yellow solid. ¹H NMR (DMSO-d₆) δ 12.16 (s, 1H), 8.92 (s,1H), 8.59 (d, 1H, J=6.4 Hz), 8.53 (dd, 1H, J=7.2, 2 Hz), 8.47 (d, 1H,J=2.4 Hz), 8.10 (dd, 1H, J=6.4, 2 Hz), 8.04 (d, 1H, J=12 Hz), 7.99 (dd,1H, J=8.8, 2.4 Hz), 7.54-7.46 (m, 7H), 7.20 (d, 1H, J=6.4 Hz), 7.97 (d,1H, J=9.2 Hz), 6.68 (t, 1H, J=6.8 Hz), 3.82-3.80 (m, 4H), 3.12 (m, 4H);MS (ESI⁺) m/z 545.19 (M+H)⁺.

Example 63

N¹—((R)-2-Amino-2-oxo-1-phenylethyl)-N³-(3-fluoro-4-(3-(6-(piperazin-1-yl)pyridin-3-yl)pyridin-4-yloxy)phenyl)malonamide,hydrochloride salt

To tert-butyl4-(5-(4-(4-amino-2-fluorophenoxy)pyridin-3-yl)pyridin-2-yl)piperazine-1-carboxylate(Compound B of Example 61, 32 mg, 0.069 mmol) in THF (1 mL) was addedDIPEA (60 uL, 0.35 mmol) then ethyl 3-chloro-3-oxopropanoate (Aldrich,10 uL, 0.076 mmol). After stirring at rt for 2 h, the reaction wasdiluted with EtOAc (5 mL), washed with saturated aqueous sodiumbicarbonate solution (1×5 mL), dried over anhydrous Na₂SO₄, andconcentrated in vacuo. The resulting yellow oil (65 mg) was dissolved inTHF (2 mL) and then charged with 1 N aqueous sodium hydroxide solution(2 mL). The solution was stirred at rt for 6 h. The solution wasconcentrated to remove THF and then acidified to pH 4-5 with 1 N aqueousHCl solution. The solid was collected by vacuum filtration and washedwith water to give the corresponding acid as a white solid (30 mg, 78% 2steps). MS (ESI⁺) m/z 552.21 (M+H)⁺.

The above acid was coupled with D(−)-phenylglycinamide (Bachem) usingTBTU as described above to give the HCl salt of the title compound (32%)as a white solid. ¹H NMR (DMSO-d₆) δ 10.64 (s, 1H), 8.89 (s, 1H), 8.74(d, 1H, J=8 Hz), 8.56 (d, 1H, J=5.6 Hz), 8.46 (d, 1H, J=2.4 Hz), 7.96(d, 1H, J=8.8 Hz), 7.84 (d, 1H, J=12 Hz), 7.74 (s, 1H), 7.46-7.37 (m,4H), 7.31-7.22 (m, 5H), 7.06 (d, 1H, J=9.2 Hz), 5.34 (d, 1H, J=8 Hz),3.81-3.78 (m, 4H), 3.40 (s, 2H), 3.12 (m, 4H); MS (ESI⁺) m/z 584.25(M+H)⁺.

Example 64

1-(3-Fluoro-4-(3-(pyridin-3-yl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea,hydrochloride salt

A) 3-(4-(2-Fluoro-4-nitrophenoxy)pyridin-3-yl)pyridine

Prepared in a similar manner as Step A of Example 59 give the titlecompound as a colorless oil. ¹H NMR (CD₃OD) δ 8.83 (d, 1H, J=1.6 Hz),8.69 (s, 1H), 8.61 (d, 1H, J=5 Hz), 8.56 (d, 1H, J=5.8 Hz), 8.27 (dd,1H, J=10.4, 2.8 Hz), 8.20-814 (m, 2H), 7.72-7.55 (m, 1H), 7.53 (t, 1H,J=8.6 Hz), 7.08 (d, 1H, J=6 Hz); MS (ESI⁺) m/z 312.15 (M+H)⁺.

B) 3-Fluoro-4-(3-(pyridin-3-yl)pyridin-4-yloxy)benzenamine

Prepared in a similar manner as Step C of Example 59 give the titlecompound as a colorless oil. MS (ESI⁺) m/z 282.12 (M+H)⁺.

C)1-(3-Fluoro-4-(3-(pyridin-3-yl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea

Prepared in a similar manner as Step C of Example 59 give to give theHCl salt of the title compound (47% combined yield for Steps B and C) asa yellow solid. ¹H NMR (DMSO-d₆) δ 11.14 (s, 1H), 10.73 (s, 1H), 9.16(d, 1H, J=1.6 Hz), 9.08 (s, 1H), 8.90 (dd, 1H, J=5.2, 1.2 Hz), 8.78 (d,1H, J=6.4 Hz), 8.56 (d, 1H, J=8 Hz), 7.95-7.90 (m, 2H), 7.60 (t, 1H,J=8.8 Hz), 7.55-7.52 (m, 1H), 7.44-7.41 (m, 2H), 7.26-7.21 (m, 3H), 3.82(s, 2H); MS (ESI⁺) m/z 461.16 (M+H)⁺.

Example 65

1-(3-Fluoro-4-(3-(4-(piperazin-1-yl)phenyl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea,trihydrochloride salt

A) tert-Butyl4-(4-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)phenyl)piperazine-1-carboxylate

Prepared in a similar manner as Step A of Example 59 give the titlecompound as a colorless oil. ¹H NMR (CD₃OD) δ 8.48 (s, 1H), 8.32 (d, 1H,J=5.6 Hz), 8.08 (dd, 1H, J=12, 4 Hz), 7.97 (d, 1H, J=8 Hz), 7.38 (d, 2H,J=8.8 Hz), 7.21-7.18 (m, 1H), 6.95-6.92 (m, 3H), 3.46 (m, 4H), 3.09-3.06(m, 4H), 1.10 (s, 9H); MS (ESI⁺) m/z 495.23 (M+H)⁺.

B) tert-Butyl4-(4-(4-(4-amino-2-fluorophenoxy)pyridin-3-yl)phenyl)piperazine-1-carboxylate

Prepared in a similar manner as Step C of Example 59 to give the titlecompound (94% combined yield for Steps A and B) as a colorless oil. ¹HNMR (CD₃OD) δ 8.30 (s, 1H), 8.14 (d, 1H, J=5.6 Hz), 7.45 (d, 2H, J=8.8Hz), 6.98 (d, 2H, J=8.8 Hz), 6.83 (t, 1H, J=8.8 Hz), 6.58 (d, 1H, J=5.6Hz), 6.48 (dd, 1H, J=12.8, 2.4 Hz), 6.43-6.41 (m, 1H), 3.49 (m, 4H),3.11-3.09 (m, 4H), 1.16 (s, 9H); MS (ESI⁺) m/z 465.24 (M+H)⁺.

C)1-(3-Fluoro-4-(3-(4-(piperazin-1-yl)phenyl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea

Prepared in a similar manner as Step C of Example 59 to give the HClsalt of the title compound (37%) as a pale yellow solid. ¹H NMR(DMSO-d₆) δ 11.01 (s, 1H), 10.60 (s, 1H), 8.77 (s, 1H), 8.51 (d, 1H,J=6.4 Hz), 7.78 (d, 1H, J=12 Hz), 7.59 (d, 2H, J=8.4 Hz), 7.44-7.40 (m,2H), 7.31-7.28 (m, 2H), 7.13-7.08 (m, 4H), 7.03 (d, 1H, J=6.4 Hz), 3.70(s, 2H), 3.42 (m, 4H), 3.15 (m, 4H); MS (ESI⁺) m/z 544.26 (M+H)⁺.

Example 66

N-(3-Fluoro-4-(3-(4-(piperazin-1-yl)phenyl)pyridin-4-yloxy)phenyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide,trihydrochloride salt

Prepared in a manner similar to that of Example 62 to give the HCl saltof the title compound (43%) as a pale yellow solid. ¹H NMR (DMSO-d₆) δ12.15 (s, 1H), 8.83 (s, 1H), 8.56-8.52 (m, 2H), 8.10 (dd, 1H, J=6.8, 2.4Hz), 8.04 (dd, 1H, J=11.6, 2 Hz), 7.61 (d, 2H, J=8.8 Hz), 7.55-7.45 (m,7H), 7.15 (d, 1H, J=6.8 Hz), 7.09 (d, 2H, J=8.8 Hz), 6.61 (t, 1H, J=6.8Hz), 3.44 (m, 4H), 3.15 (m, 4H); MS (ESI⁺) m/z 562.36 (M+H)⁺.

Example 67

N-(3-Fluoro-4-(3-(4-(2-hydroxyethyl)phenyl)pyridin-4-yloxy)phenyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

A)3-(4-(2-(tert-Butyldimethylsilyloxy)ethyl)phenyl)-4-(2-fluoro-4-nitrophenoxy)pyridine

Prepared in a similar manner as Step A of Example 59 to give the titlecompound (77%) as a colorless oil. ¹H NMR (CD₃OD) δ 8.67 (s, 1H), 8.56(d, 1H, J=8 Hz), 8.27 (dd, 1H, J=12, 4 Hz), 8.16 (d, 1H, J=8 Hz), 7.58(d, 2H, J=8 Hz), 7.39 (d, 2H, J=8 Hz), 7.36 (m, 1H), 7.15 (d, 1H, J=4Hz), 3.91 (t, 2H, J=8 Hz), 2.90 (t, 2H, J=8 Hz), 0.90 (s, 9H), 0.00 (s,6H); MS (ESI⁺) m/z 469.25 (M+H)⁺.

B)3-(4-(2-(tert-Butyldimethylsilyloxy)ethyl)phenyl)-4-(2-fluoro-4-nitrophenoxy)pyridine

Prepared in a similar manner as Step C of Example 59 to give the titlecompound (76%) as a pale yellow oil. ¹H NMR (CD₃OD) δ 8.44 (s, 1H), 8.32(d, 1H, J=4 Hz), 7.57 (d, 2H, J=8 Hz), 7.36 (d, 2H, J=8.4 Hz), 6.95 (t,1H, J=8 Hz), 6.75 (d, 1H, J=4 Hz), 6.61 (d, 1H, J=8 Hz), 6.55 (d, 1H,J=4 Hz), 3.90 (t, 2H, J=6.8 Hz), 2.89 (t, 2H, J=6.4 Hz), 0.87 (s, 9H),0.00 (s, 6H); MS (ESI⁺) m/z 439.26 (M+H)⁺.

C)N-(3-Fluoro-4-(3-(4-(2-hydroxyethyl)phenyl)pyridin-4-yloxy)phenyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

Prepared in a similar manner as Step C of Example 62. After amideformation, the resulting yellow oil was dissolved in THF (2 mL) and thentreated with TBAF (Aldrich, 180 uL, 1 M in THF) at rt for 1 h. Thereaction was diluted with EtOAc (10 mL), washed successively with waterand brine (5 mL each), dried over anhydrous Na₂SO₄, and concentrated invacuo. The crude product was purified by flash chromatography on silicagel (10% methanol/EtOAc) to give the title compound (72%) as a paleyellow solid. ¹H NMR (CD₃OD) δ 8.59 (dd, 1H, J=7.6, 2.0 Hz), 8.41 (s,1H), 8.26 (d, 1H, J=5.6 Hz), 7.91-7.85 (m, 2H), 7.55-7.46 (m, 5H), 7.41(d, 2H, J=6.7 Hz), 7.29 (d, 2H, J=8.1 Hz), 7.26 (m, 1H), 7.13 (t, 1H,J=8.7 Hz), 6.69 (d, 1H, J=6 Hz), 6.64 (t, 1H, J=7.2 Hz), 3.73 (t, 2H,J=7.2 Hz), 2.82 (t, 2H, J=6.8 Hz); MS (ESI⁺) m/z 522.27 (M+H)⁺.

Example 68

N-(4-(3-(4-(2-Aminoethyl)phenyl)pyridin-4-yloxy)-3-fluorophenyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide,dihydrochloride salt

ToN-(3-fluoro-4-(3-(4-(2-hydroxyethyl)phenyl)pyridin-4-yloxy)phenyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide(Compound C of Example 67, 40 mg, 0.077 mmol) in THF (1 mL) was addedDIPEA (27 uL, 0.154 mmol) followed by methanesulfonyl chloride (Aldrich,7 uL, 0.092 mmol). After stirring at rt for 30 min, the reaction wasconcentrated in vacuo. The residue was dissolved in 3 mL of ethanol andtransferred to a pressure tube. Ammonium hydroxide (7 mL) was added andthe tube was sealed and heated at 50° C. for 8 h. After cooling to rt,the reaction was diluted with EtOAc (10 mL), washed with water (2×10 mL)then brine (1×10 mL), dried over anhydrous Na₂SO₄, and concentrated invacuo. The crude product was purified by prep HPLC. The appropriatefractions were concentrated to remove methanol and basified withsaturated sodium bicarbonate solution. The aqueous layer was extractedwith EtOAc (2×20 mL) and the pooled organic extracts were washed withbrine (1×10 mL), dried over anhydrous Na₂SO₄, and concentrated. Theresidue was dissolved in dioxane (2 mL) and charged with 1N HCl in ether(1 mL). The solution was concentrated and the resulting solid waslyophilized from acetonitrile/water to give the HCl salt of the titlecompound (24 mg, 53%) as a white solid. ¹H NMR (DMSO-d₆) δ 12.13 (s,1H), 8.74 (s, 1H), 8.55-8.51 (m, 2H), 8.09 (dd, 1H, J=6.4, 2 Hz), 8.03(m, 1H), 7.64 (d, 2H, J=6 Hz), 7.63 (m, 1H), 7.54-7.41 (m, 6H), 7.38 (d,2H, J=8.4 Hz), 7.04 (d, 1H, J=6 Hz), 6.68 (t, 1H, J=6.8 Hz), 3.02 (m,2H), 2.89 (m, 2H); MS (ESI⁺) m/z 521.27 (M+H)⁺.

Example 69

N-(4-(3-(4-((2-(Methylamino)ethyl)carbamoyl)phenyl)pyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide,dihydrochloride salt

A) Methyl 4-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)benzoate

Prepared in a similar manner as Step A of Example 59 to give the titlecompound (77%) as a colorless oil. ¹H NMR (CD₃OD) δ 8.66 (s, 1H), 8.52(d, 1H, J=6 Hz), 8.22 (dd, 1H, J=10.4, 2.8 Hz), 8.16-8.13 (m, 1H), 8.10(d, 2H, J=8.4 Hz), 7.97 (d, 2H, J=8 Hz), 7.44 (t, 1H, J=8.5 Hz), 7.06(d, 1H, J=6 Hz), 3.93 (s, 3H); MS (ESI⁺) m/z 369.22 (M+H)⁺.

B) Methyl 4-(4-(4-amino-2-fluorophenoxy)pyridin-3-yl)benzoate

Prepared in a similar manner as Step C of Example 59 to give the titlecompound (99%) as a yellow oil. ¹H NMR (CD₃OD) δ 8.38 (s, 1H), 8.24 (d,1H, J=6 Hz), 8.01 (d, 2H, J=8.4 Hz), 7.66 (d, 2H, J=8.4 Hz), 6.85 (t,1H, J=9.2 Hz), 6.65 (d, 1H, J=6 Hz), 6.48 (dd, 1H, J=12.8, 2.4 Hz), 6.43(d, 1H, J=2.8 Hz), 3.82 (s, 3H); MS (ESI⁺) m/z 339.28 (M+H)⁺.

C) Methyl4-(4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)pyridin-3-yl)benzoate

Prepared in a similar manner as Step C of Example 62 to give the titlecompound (81%) as a yellow oil. ¹H NMR (CD₃OD) δ 8.66 (dd, 1H, J=7.2, 2Hz), 8.56 (s, 1H), 8.40 (d, 1H, J=6 Hz), 8.13 (d, 2H, J=8.4 Hz),7.97-7.95 (m, 2H), 7.78 (d, 2H, J=8.4 Hz), 7.55-7.52 (m, 2H), 7.38-7.31(m, 3H), 7.26 (t, 1H, J=7.2 Hz), 6.82 (d, 1H, J=5.6 Hz), 6.72 (t, 1H,J=6.7 Hz), 3.94 (s, 3H); MS (ESI⁺) m/z 554.21 (M+H)⁺.

D)N-(4-(3-(4-((2-(Methylamino)ethyl)carbamoyl)phenyl)pyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

To the above ester (159 mg, 0.29 mmol) in THF (5 mL) was added 1 Naqueous NaOH (5 mL). After stirring at rt for 20 h, the reaction wasconcentrated to remove THF. The aqueous solution was acidified to pH 4with 1 N aqueous HCl. The acid was collected by filtration and washedwith water to give the desired product (144 mg, 92%) as a tan solid. MS(ESI⁺) m/z 540.21 (M+H)⁺.

The amide was prepared as described above using TBTU to give the HClsalt of the title compound (62%) as a white solid. ¹H NMR (DMSO-d₆) δ12.21 (s, 1H), 8.93-8.90 (m, 2H), 8.68-8.64 (m, 2H), 8.21 (dd, 1H,J=6.4, 2 Hz), 8.16 (m, 1H), 8.11 (d, 2H, J=8 Hz), 7.90 (d, 2H, J=8.4Hz), 7.69-7.65 (m, 2H), 7.60-7.47 (m, 4H), 7.16 (d, 1H, J=5.6 Hz), 6.80(t, 1H, J=7 Hz), 3.64 (t, 2H, J=5.2 Hz), 3.17 (t, 2H, J=5.2 Hz), 2.65(s, 3H); MS (ESI⁺) m/z 596.37 (M+H)⁺.

Example 70

N-(4-(3-(4-((2-Aminoethyl)carbamoyl)phenyl)pyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide,dihydrochloride salt

Prepared in a similar manner as Example 69 to give the HCl salt of thetitle compound as an off-white solid. ¹H NMR (DMSO-d₆) δ 12.17 (s, 1H),8.87-8.85 (m, 2H), 8.64 (d, 1H, J=6.4 Hz), 8.59 (dd, 1H, J=7.6, 2.4 Hz),8.16 (dd, 1H, J=6.8, 2.4 Hz), 8.10 (m, 1H), 8.06 (d, 2H, J=8.4 Hz), 8.00(br s, 2H), 7.85 (d, 2H, J=8.4 Hz), 7.64-7.60 (m, 2H), 7.55-7.42 (m,4H), 7.13 (d, 1H, J=6 Hz), 6.75 (t, 1H, J=7.2 Hz), 3.56-3.53 (m, 2H),3.04-2.99 (m, 2H); MS (ESI⁺) m/z 582.32 (M+H)⁺.

Example 71

N-(4-(3-(4-((2-(Dimethylamino)ethyl)carbamoyl)phenyl)pyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide,dihydrochloride salt

Prepared in a similar manner as Example 69 to give the HCl salt of thetitle compound (56%) as an off-white solid. ¹H NMR (DMSO-d₆) δ 12.08 (s,1H), 8.87 (br s, 1H), 8.75 (s, 1H), 8.54-8.51 (m, 2H), 8.08 (dd, 1H,J=6.8, 2.4 Hz), 8.02 (m, 1H), 7.99 (d, 2H, J=8.4 Hz), 7.77 (d, 2H, J=8.4Hz), 7.56-7.53 (m, 2H), 7.47-7.34 (m, 4H), 6.99 (d, 1H, J=5.6 Hz), 6.67(t, 1H, J=6.8 Hz), 3.61-3.57 (m, 2H), 3.23-3.21 (m, 2H), 2.77 (s, 3H),2.76 (s, 3H); MS (ESI⁺) m/z 610.30 (M+H)⁺.

Example 72

1-(4-(3-Aminopyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea

A) 3-Fluoro-4-(3-nitropyridin-4-yloxy)benzenamine

To 4-amino-2-fluorophenol (see Step A of Example 19, 127 mg, 1.0 mmol)in DMF (5 mL) at rt under nitrogen was added sodium hydride (80 mg, 2mmol, 60%). After stirring at rt for 10 min, 4-chloro-3-nitropyridinehydrochloride (Lancaster, 195 mg, 1.0 mmol) was added. The mixture wasstirred at rt for 1 h and was then diluted with EtOAc (50 mL) and washedwith water, 10% aqueous lithium chloride solution, and then brine (1×30mL each). The organic layer was dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The crude product was purified by flash columnchromatography on silica gel eluting with EtOAc to give the titlecompound (150 mg, 60%) as a yellow-orange solid. ¹H NMR (DMSO-d₆) δ 9.13(s, 1H), 8.63 (d, 1H, J=6 Hz), 7.09 (t, 1H, J=9.2 Hz), 6.92 (d, 1H, J=6Hz), 6.55 (dd, 1H, J=13.2, 2.4 Hz), 6.45 (dd, 1H, J=9.2, 2.4 Hz), 5.61(s, 2H); MS (ESI⁺) m/z 250.18 (M+H)⁺.

B)1-(3-Fluoro-4-(3-nitropyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea

A solution of 3-fluoro-4-(3-nitropyridin-4-yloxy)benzenamine (158 mg,0.63 mmol) in THF (3 mL) was treated with a solution of solution of2-(4-fluorophenyl)acetyl isocyanate in toluene (Compound D of Example11, 1.3 mmol) and stirred at room temperature for 2 h then at 50° C. for5 min. The mixture was concentrated and the residue treated with DMF (15mL) and SiO₂ (150 mg) and the mixture concentrated to dryness undervacuum and applied to a SiO₂ column. The column was eluted with 20-60%EtOAc/hexanes to give the product, which was further purified bytrituration with isopropyl ether to give a pale yellow solid (120 mg,25%). ¹H NMR (DMSO-d₆) δ 11.07 (s, 1H), 10.63 (s, 1H), 9.19 (s, 1H),8.67 (d, 1H, J=5.6 Hz), 7.85 (d, 1H, J=11.7 Hz), 7.46-7.45 (m, 2H),7.39-7.35 (m, 2H), 7.18 (dd, 2H, J=8.6, 8.6 Hz), 7.01 (d, 1H, J=6.1 Hz),3.76 (s, 2H).

C)1-(4-(3-Aminopyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea

A suspension of1-(3-fluoro-4-(3-nitropyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea(125 mg, 0.29 mmol) in 3:1 MeOH/THF (20 mL) was hydrogenated over Pt₂O(50 mg) using H₂ from a latex balloon for 6 h. The catalyst was filteredoff with the aid of Celite® and the filtrate concentrated to give thetitle compound (85 mg, 74%) as a white solid. ¹H NMR (DMSO-d₆) δ 11.03(s, 1H), 10.55 (s, 1H), 8.03 (s, 1H), 7.75 (dd, 1H, J=2.5, 13.2 Hz),7.65 (d, 1H, J=5.1 Hz), 7.38-7.35 (m, 3H), 7.23-7.16 (m, 3H), 6.42 (d,1H, J=5.1 Hz), 5.26 (s, 2H), 3.75 (s, 2H); MS (ESI⁺): m/z 399.35 (M+H)⁺.

Example 73

1-(4-(3-((1S,4S)-4-Aminocyclohexanecarboxamido)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,trifluoroacetic acid salt

A) tert-Butyl(1S,4S)-4-((4-(2-fluoro-4-(3-(2-(4-fluorophenyl)acetyl)ureido)phenoxy)pyridin-3-yl)carbamoyl)cyclohexylcarbamate

A solution of N-Boc-cis-1,4-diaminocyclohexane carboxylic acid(Chem-Imprex International, 24 mg, 0.10 mmol) in THF (1 mL) was cooledto 0° C., and treated with Et₃N and then isobutylchloroformate. After 5min, the mixture was treated with a solution of1-(4-(3-aminopyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea(Compound C of Example 72, 27 mg, 0.068 mmol) in THF (0.5 mL) and thestirring continued at 0° C. for 10 min and then at room temperature for2 h. The mixture was partitioned between EtOAc and saturated aq. NaHCO₃solution and the EtOAc phase separated, dried (MgSO₄) and concentratedin vacuo to give the crude product. Purification of the residue by flashcolumn chromatography on SiO₂ eluting with 50-100% EtOAc/hexanes gavethe title compound (13 mg, 21%) as a white solid. MS (ESI⁺): m/z 624.25(M+H)⁺.

B)1-(4-(3-((1S,4S)-4-Aminocyclohexanecarboxamido)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,trifluoroacetic acid salt

A solution of tert-butyl(1S,4S)-4-((4-(2-fluoro-4-(3-(2-(4-fluorophenyl)acetyl)ureido)phenoxy)pyridin-3-yl)carbamoyl)cyclohexylcarbamate(10 mg, 0.016 mmol) in anhydrous MeOH (0.5 mL) was cooled to 0° C. andtreated with 4 M HCl/1,4-dioxane (2 mL). The mixture was stirred at 0°C. for 1.5 h and then at room temperature for 20 min and finallyconcentrated in vacuo to give the crude product. Purification of theresidue by preparative HPLC (Column A) gave the title compound (4 mg,33%) as a yellow solid. ¹H NMR (DMSO-d₆) δ 11.07 (s, 1H), 10.64 (s, 1H),9.28 (s, 1H), 8.40-8.37 (m, 1H), 7.94 (s, 1H), 7.83 (dd, 1H, J=2.1, 12.7Hz), 7.47-7.33 (m, 5H), 7.19-7.14 (m, 3H), 7.07-7.02 (m, 1H), 3.75 (s,2H), 3.25-3.15 (m, 1H), 2.85-2.76 (m, 1H), 1.97-1.84 (m, 2H), 1.85-1.61(m, 5H); MS (ESI⁺): m/z 524.26 (M+H)⁺.

Example 74

1-(4-(3-((1R,4R)-4-Aminocyclohexanecarboxamido)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,bis-trifluoroacetic acid salt

A) tert-Butyl(1R,4R)-4-((4-(2-fluoro-4-(3-(2-(4-fluorophenyl)acetyl)ureido)phenoxy)pyridin-3-yl)carbamoyl)cyclohexylcarbamate

The title compound was prepared from1-(4-(3-aminopyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea(Compound C of Example 72, 57 mg, 0.14 mmol) andN-Boc-trans-4-aminocyclohexane-1-carboxylic acid (Anaspec Inc., 51 mg,0.21 mmol) in a similar manner as described for Step A of Example 73 togive the title compound (32 mg, 66%) as white solid. MS (ESI⁺): m/z624.41 (M+H)⁺.

B)1-(4-(3-((1R,4R)-4-Aminocyclohexanecarboxamido)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,bis-trifluoroacetic acid salt

The title compound was prepared from tert-butyl(1S,4S)-4-((4-(2-fluoro-4-(3-(2-(4-fluorophenyl)acetyl)ureido)phenoxy)pyridin-3-yl)carbamoyl)cyclohexylcarbamate(25 mg) in a similar manner as described for Example 73. Purification ofthe reaction mixture by preparative HPLC (Column A) gave the titlecompound (7 mg, 23%) as a white solid. ¹H NMR (DMSO-d₆) δ 11.06 (s, 1H),10.61 (s, 1H), 9.94 (s, 1H), 9.19 (s, 1H), 8.28 (d, 1H, J=5.6 Hz), 7.82(dd, 1H, J=2.0, 13.2 Hz), 7.79-7.76 (m, 3H), 7.43 (dd, 1H, J=2.0, 8.6Hz), 7.38-7.33 (m, 2H), 7.17 (dd, 2H, J=9.2, 6.6 Hz), 6.86 (d, 1H, J=5.6Hz), 3.74 (s, 2H), 3.08-2.95 (m, 1H), 2.67-2.43 (m, 1H), 2.01-1.88 (m,4H), 1.53-1.43 (m, 2H), 1.37-1.27 (m, 2H); MS (ESI⁺): m/z 524.35 (M+H)⁺.

Example 75

1-(4-(3-((1R,4R)-4-(Aminomethyl)cyclohexanecarboxamido)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea

A) Benzyl((1R,4R)-4-((4-(2-fluoro-4-(3-(2-(4-fluorophenyl)acetyl)ureido)phenoxy)pyridin-3-yl)carbamoyl)cyclohexyl)methylcarbamate

The title compound was prepared from1-(4-(3-aminopyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea(Compound C of Example 72, 50 mg, 0.13 mmol) andtrans-4-((benzyloxycarbonyl)methyl)cyclohexanecarboxylic acid (40 mg,0.14 mmol, prepared according to the synthetic route described inSchaus, J. M. et al. J. Med. Chem. 1998, 41, 1943-1955) according toStep A of Example 73 to give the title compound (30 mg, 34%) as whitesolid. MS (ESI⁺): m/z 672.34 (M+H)⁺.

B)1-(4-(3-((1R,4R)-4-(Aminomethyl)cyclohexanecarboxamido)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea

A solution ofbenzyl((1R,4R)-4-((4-(2-fluoro-4-(3-(2-(4-fluorophenyl)acetyl)ureido)phenoxy)pyridin-3-yl)carbamoyl)cyclohexyl)methylcarbamate(25 mg 0.037 mmol) in MeOH (1.5 mL) was hydrogenated over 10%palladium-carbon (15 mg) for 4 h using H₂ form a rubber balloon. Thecatalyst was filtered off and the filtrate concentrated in vacuo to givethe title compound (18 mg, 90%) as a yellow solid. ¹H NMR (DMSO-d₆) δ10.62 (s, 1H), 9.64 (s, 1H), 9.01 (s, 1H), 8.17 (d, 1H, J=5.6 Hz), 7.79(dd, 1H, J=2.5, 12.7 Hz), 7.42-7.35 (m, 4H), 7.30 (dd, 1H, J=8.6, 9.2Hz), 7.18 (m, 2H), 6.66 (d, 1H, J=5.6 Hz), 3.75 (s, 2H), 2.39 (d, 2H,J=6.6 Hz), 1.87-1.81 (m, 4H), 1.46-1.35 (m, 1H), 1.33-1.10 (m, 1H),0.95-0.77 (m, 4H); MS (ESI⁺): m/z 538.28 (M+H)⁺.

Example 76

1-(4-(3-(Cyclohexanecarboxamido)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea

A solution of1-(4-(3-aminopyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea(Compound C of Example 72, 25 mg, 0.062 mmol) in CH₂Cl₂ (2 mL) wastreated with Et₃N (10 μL, 0.074 mmol) and cyclohexanecarbonyl chloride(Aldrich, 11 mg, 0.074 mmol) and stirred at rt for 2 h. An additionalportion of cyclohexanecarbonyl chloride (11 mg, 0.074 mmol) was added tothe mixture and the reaction continued for 18 h. The mixture was dilutedwith CH₂Cl₂, washed with saturated aq. NaHCO₃ solution, dried (MgSO₄)and concentrated in vacuo. The residue was purified by flash columnchromatography on SiO₂ eluting with 50-100% EtOAc/hexanes to give thetitle compound (19 mg, 61%) as a white solid. ¹H NMR (DMSO-d₆) δ 11.03(s, 1H), 10.57 (m, 1H), 9.60 (m, 1H), 8.99 (s, 1H), 8.15 (d, 1H, J=5.6Hz), 7.76 (dd, 1H, J=2.0, 13.2 Hz), 7.39-7.33 (m, 3H), 7.28 (dd, 1H,J=8.6, 9.2 Hz), 7.18-7.14 (m, 2H), 6.65 (d, 1H, J=5.1 Hz), 3.73 (s, 2H),1.81-1.71 (m, 5H), 1.64-1.61 (m, 1H), 1.43-1.34 (m, 2H), 1.29-1.14 (m,3H); MS (ESI⁺): m/z 509.27 (M+H)⁺.

Example 77

1-(4-(3-(4-Aminopiperidine-1-carboxamido)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,bis-trifluoroacetic acid salt

A)1-(3-Fluoro-4-(3-(4-(2-phenoxyacetamido)piperidine-1-carboxamido)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea

A solution of triphosgene (50 mg, 0.17 mmol), in CH₂Cl₂ (0.4 mL) wascooled to −10° C. and treated with a solution of1-(4-(3-aminopyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea(Compound C of Example 72, 67 mg, 0.17 mmol) and DIPEA (65 μL, 0.37mmol) in CH₂Cl₂ (0.4 mL). The mixture was stirred at −10° C. for 10 minand then treated with a solution of 4-((carbobenzyloxy)amido)piperidine(40 mg, 0.17 mmol, prepared using the procedure describe in Schaus, J.M. et al. J. Med. Chem. 1998, 41, 1943-1955) and DIPEA (65 μl, 0.37mmol) in CH₂Cl₂ (0.4 mL). After stirring for 2 minutes, the mixture waswarmed to room temperature then heated to 40° C. for 10 min. The mixturewas diluted with EtOAc, washed with saturated aq. NaHCO₃ and brine,dried (MgSO₄) and concentrated in vacuo. The product was purified byflash column chromatography on SiO₂ eluting with 0-5% MeOH/CH₂Cl₂ togive the title compound (50 mg, 45%) as yellow solid. MS (ESI⁺) m/z659.29 (M+H)⁺.

B)1-(4-(3-(4-Aminopiperidine-1-carboxamido)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,bis-trifluoroacetic acid salt

A solution of1-(3-fluoro-4-(3-(4-(2-phenoxyacetamido)piperidine-1-carboxamido)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea(45 mg, 0.068 mmol) in absolute MeOH (2.5 mL) was hydrogenated over 10%palladium-carbon (15 mg) using H₂ from a rubber balloon for 2.5 h. Thecatalyst was filtered and the filtrate concentrated in vacuo and theresidue was purified by preparative HPLC (Column A) to afford the titlecompound. ¹H NMR (DMSO-d₆) δ 10.57 (s, 1H), 8.55 (s, 1H), 8.27 (m, 1H),8.14 (d, 1H, J=5.6 Hz), 7.75 (dd, 1H, J=2.0, 12.7 Hz), 7.37-7.33 (m,3H), 7.23-7.14 (m, 3H), 6.65 (d, 1H, J=5.1 Hz), 4.05-3.98 (m, 2H), 3.73(s, 2H), 3.05-2.91 (m, 1H), 2.88-2.83 (m, 2H), 1.83-1.74 (m, 2H),1.34-1.20 (m, 2H); MS (ESI⁺) m/z 525.35 (M+H)⁺.

Example 78

1-(4-(2-Amino-3-(4-(2-amino-2-oxoethyl)phenyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,trifluoroacetic acid salt

A) 2-(4-(2-Amino-4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)phenyl)aceticacid

A mixture of 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridin-2-amine (CompoundC of Example 34, 88 mg, 0.23 mmol), 4-(dihydroxyborane)phenylacetic acidpinacol ester (Frontier Scientific Inc., 92 mg, 0.35 mmol), Na₂CO₃ (170mg, 1.61 mmol), 1,4-dioxane (2 mL) and H₂O (2 mL) was degassed byvacuum/argon purge and treated with tetrakis(triphenylphosphine)palladium (27 mg, 0.023 mmol). After heating at 100° C. for 3 h, the pHof the mixture was adjusted to pH 6 using 1 N hydrochloric acid. Themixture was concentrated in vacuo and the residue partitioned betweenEtOAc and pH 7 phosphate buffer. The aqueous phase was extracted withEtOAc and the combined extracts were dried (MgSO₄) and concentrated invacuo to give the crude product. The product was triturated with 2:1EtOAc/MeOH to give the desired product (70 mg, 80%) as an orange-brownsolid. ¹H NMR (DMSO-d₆) δ 12.34 (s, 1H), 8.23 (dd, 1H, J=3.1, 10.5 Hz),8.05 (d, 1H, J=10.2 Hz), 7.94 (d, 1H, J=6.1 Hz), 7.32-7.25 (m, 5H), 6.26(d, 1H, J=6.1 Hz), 5.62 (s, 2H), 3.57 (s, 2H); MS (ESI⁺): m/z 384.16(M+H)⁺.

B)2-(4-(2-Amino-4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)phenyl)acetamide

A solution of2-(4-(2-amino-4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)phenyl)acetic acid(65 mg, 0.17 mmol) in anhydrous DMF (1.2 mL) was treated with PyBOP (125mg, 0.24 mmol) and HOBt (32 mg, 0.24 mmol) followed by DIPEA (60 μL,0.35 mmol) and NH₄Cl (19 mg, 0.35 mmol). After stirring at roomtemperature for 20 min, the mixture was concentrated under vacuum andthe residue partitioned between EtOAc and saturated aq. NaHCO₃ solution.The EtOAc phase was washed with brine, dried (MgSO₄) and concentrated invacuo. The product was purified by flash column chromatography on SiO₂eluting with 0-8% MeOH/CH₂Cl₂ to give the title compound (40 mg, 62%) asan amber colored oil. ¹H NMR (DMSO-d₆) δ 8.23 (dd, 1H, J=10.7, 2.5 Hz),8.05 (d, 1H, J=9.2 Hz), 7.93 (d, 1H, J=6.1 Hz), 7.42-7.32 (m, 2H),7.33-7.25 (m, 4H), 6.92 (s, 1H), 6.25 (d, 1H, J=5.6 Hz), 5.64 (s, 2H),3.36 (s, 2H); MS (ESI⁺): m/z 383.17 (M+H)⁺.

C)2-(4-(2-Amino-4-(4-amino-2-fluorophenoxy)pyridin-3-yl)phenyl)acetamide

A mixture of2-(4-(2-amino-4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)phenyl)acetamide(32 mg, 0.086 mmol), DMF (1 mL), EtOH (1 mL) and H₂O (1 mL) was treatedwith Fe powder (67 mg, 1.2 mmol), and NH₄Cl (128 mg, 2.4 mmol) and themixture heated at 100° C. for 20 min. The mixture was filtered throughCelite®, the pH of the filtrate adjusted to pH 7 using phosphate bufferand then the mixture was extracted with EtOAc. The organic extract wasdried (MgSO₄) and concentrated to give the desired product (20 mg, 67%)as a yellow-brown solid. MS (ESI⁺): m/z 353.32 (M+H)⁺.

D)1-(4-(2-Amino-3-(4-(2-amino-2-oxoethyl)phenyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)ureatrifluoroacetic acid salt

The title compound was prepared form2-(4-(2-amino-4-(4-amino-2-fluorophenoxy)pyridin-3-yl)phenyl)acetamide(19 mg, 0.054 mmol) and 0.3 M solution of 2-(4-fluorophenyl)acetylisocyanate in toluene (Compound D of Example 11, 0.27 mL, 0.081 mmol) ina similar manner as that described for Step D of Example 33.Purification of the reaction mixture by preparative HPLC (Column A) gavethe title compound (9 mg, 26%) as a white solid. ¹H NMR (DMSO-d₆): δ11.03 (s, 1H), 10.57 (s, 1H), 7.93 (d, 1H, J=7.1 Hz), 7.76 (dd, 1H,J=2.0, 13.2 Hz), 7.44-7.42 (m, 3H), 7.37-7.29 (m, 6H), 7.16 (dd, 2H,J=8.6, 8.8 Hz), 6.94 (s, 1H), 6.31 (d, 1H, J=7.1 Hz), 3.72 (s, 2H), 3.43(s, 2H); MS (ESI⁺): m/z 532.24 (M+H)⁺.

Example 79

1-(4-(2-Amino-3-(2-(pyridin-2-yl)ethynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,dihydrochloride salt

A)4-(2-Fluoro-4-nitrophenoxy)-3-(2-(pyridin-2-yl)ethynyl)pyridin-2-amine

A mixture of 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridin-2-amine (CompoundC of Example 34, 100 mg, 0.27 mmol) and 2-ethynylpyridine (Aldrich, 57mg, 0.54 mmol), THF (2 mL) and Et₃N (2 mL) was degassed by vacuum/argonpurge and treated in turn with CuI (6 mg, 0.032 mmol) and (Ph₃P)₄Pd (20mg, 0.017 mmol). The mixture was heated at 60° C. for 45 minutes,cooled, partitioned between EtOAc and saturated aq. sodium bicarbonatesolution. The organic phase was dried (MgSO₄) and concentrated in vacuoto give the crude product. Purification of the residue by flash columnchromatography on SiO₂ eluting with 0-1.5% MeOH/CH₂Cl₂ gave the titlecompound (55 mg, 58%) as a brown solid. ¹H NMR (DMSO-d₆) δ 8.53 (d, 1H,J=5.1 Hz), 8.39 (dd, 1H, J=2.5, 10.7 Hz), 8.15 (dm, 1H, J=8.1 Hz), 7.97(d, 1H, J=5.6 Hz), 7.81 (d, 1H, J=8.1 Hz), 7.71 (d, 1H, J=7.6 Hz), 7.52(dd, 1H, J=8.6, 8.6 Hz), 7.38-7.34 (m, 1H), 6.71 (s, 2H), 6.21 (d, 1H,J=5.6 Hz); MS (ESI⁺): m/z 351.25 (M+H)⁺.

B)4-(4-Amino-2-fluorophenoxy)-3-(2-(pyridin-2-yl)ethynyl)pyridin-2-amine

A mixture of4-(2-fluoro-4-nitrophenoxy)-3-(2-(pyridin-2-yl)ethynyl)pyridin-2-amine(35 mg, 0.1 mmol), THF (1.5 mL) and MeOH (1.5 ml) was treated with zincdust (65 mg, 1.0 mmol) and NH₄Cl (53 mg, 1.0 mmol) and heated at 60° C.for 45 min. The reaction mixture was cooled, filtered and concentratedunder vacuum. The residue was partitioned between EtOAc and saturatedaq. NaHCO₃ solution. The organic phase was separated, washed with brine,dried (MgSO₄) and concentrated to give the title compound (25 mg, 78%)as a brown solid. MS (ESI⁺): m/z 321.2 (M+H)⁺.

C)1-(4-(2-Amino-3-(2-(pyridin-2-yl)ethynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,dihydrochloride salt

A solution of4-(4-amino-2-fluorophenoxy)-3-(2-(pyridin-2-yl)ethynyl)pyridin-2-amine(25 mg, 0.078 mmol) in THF (2 mL) was cooled to 0° C. and treated with0.3 M solution of 2-(4-fluorophenyl)acetyl isocyanate in toluene(Compound D of Example 11, 0.26 mL, 0.078 mmol). After 1 h, the mixturewas warmed to room temperature and stirred for 15 min. The mixture wasconcentrated under vacuum and the residue purified by preparative HPLC(Column A) to give the title compound as a TFA salt. The TFA salt wasdissolved in anhydrous MeOH and treated with 1 M HCl/Et₂O at 0° C. andstirred for 5 min. The mixture was then concentrated in vacuo to givethe title compound (18 mg, 41%) as a brown solid. ¹H NMR (DMSO-d₆) δ11.06 (s, 1H), 10.63 (s, 1H), 8.62 (d, 1H, J=4.5 Hz), 8.22 (s, 2H), 7.99(d, 1H, J=7.1 Hz), 7.94-7.81 (m, 3H), 7.48-7.44 (m, 3H), 7.37-7.33 (m,2H), 7.16 (dd, 2H, J=6.2, 9.2 Hz), 6.30 (d, 1H, J=7.1 Hz), 3.74 (s, 2H);MS (ESI⁺): m/z 500.21 (M+H)⁺.

Example 80

1-(4-(2-Acetamidopyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,hydrochloride salt

A) tert-Butyl 4-(2-carbamoylpyridin-4-yloxy)-3-fluorophenylcarbamate

A mixture of 4-(4-amino-2-fluorophenoxy)picolinamide (Compound B′ ofExample 24, 190 mg, 0.76 mmol), tert-butyl alcohol (2 mL), 1,4-dioxane(1 mL), DMF (1 mL) and Boc₂O (167 mg, 0.76 mmol) was heated at 65° C.for 16 h. Additional portions of Boc₂O (85 mg and 60 mg) were addedafter 16 h and 32 h, respectively and the mixture heated for a total of40 h. The mixture was concentrated under vacuum and the residuepartitioned between EtOAc and saturated aq. NaHCO₃ solution. The EtOAcphase was dried (MgSO₄) and concentrated in vacuo to give the crudeproduct. Purification of the residue by flash column chromatography onSiO₂ eluting with 30-60% EtOAc/hexanes gave the title compound (180 mg,68%) as a brown solid. ¹H NMR (DMSO-d₆) δ 9.74 (s, 1H), 8.52 (d, 1H,J=5.6 Hz), 8.13 (s, 1H), 7.72 (s, 1H), 7.62 (d, 1H, J=13.7 Hz),7.35-7.31 (m, 3H), 7.18 (dd, 1H, J=5.6, 2.5 Hz), 1.39 (s, 9H); MS(ESI⁺): m/z 348.22 (M+H)⁺.

B) tert-Butyl 4-(2-aminopyridin-4-yloxy)-3-fluorophenylcarbamate

A solution of KOH (280 mg, 5.0 mmol) in H₂O (2 mL) was cooled to 0-5° C.and treated dropwise with bromine (162 mg, 1.0 mmol) and the mixturestirred for 5 min. tert-Butyl4-(2-carbamoylpyridin-4-yloxy)-3-fluorophenylcarbamate (347 mg, 1.0mmol) was added to the mixture in one portion as a solid and then1,4-dioxane (3 mL) was added to dissolve the solids. The reactionmixture was stirred at room temperature for 30 min then at 55° C. for 45min. The mixture was then cooled to room temperature, treated with HOAc(0.5 mL) and stirred until the foaming subsided. The mixture wasreheated to 55° C. for 20 min, cooled to room temperature, treated withKOH (350 mg) and extracted with CH₂Cl₂. The organic extract was dried(MgSO₄) and concentrated under vacuum. The residue was purified by flashcolumn chromatography on SiO₂ eluting with 30-70% EtOAc/hexanes to givethe title compound (265 mg, 83%). ¹H NMR (DMSO-d₆) δ 9.67 (s, 1H), 7.77(d, 1H, J=6.1 Hz), 7.56 (d, 1H, J=11.7 Hz), 7.26-7.18 (m, 2H), 6.12 (dd,1H, J=2.0, 6.1 Hz), 5.93 (s, 2H), 5.74 (d, 1H, J=2.5 Hz), 1.47 (s, 9H);MS (ESI⁺): m/z 320.23 (M+H)⁺.

C) tert-Butyl 4-(2-acetamidopyridin-4-yloxy)-3-fluorophenylcarbamate

A tert-butyl 4-(2-aminopyridin-4-yloxy)-3-fluorophenylcarbamate (150 mg,0.47 mmol) in anhydrous pyridine (0.5 mL) was cooled to 10° C. andtreated with acetyl chloride (33 μL, 0.47 mmol) and the mixture stirredfor 45 min. An additional portion of acetyl chloride (16 μL, 0.24 mmol)was added to the reaction and stirring continued for 25 min. The mixturewas diluted with EtOAc (20 mL), washed with brine, dried (MgSO₄) andconcentrated under vacuum to give the title compound (115 mg, 68%). ¹HNMR (DMSO-d₆) δ 10.55 (s, 1H), 9.71 (s, 1H), 8.16 (d, 1H, J=5.5 Hz),7.63-7.55 (m, 2H), 7.29-7.23 (m, 2H), 6.68-6.63 (m, 1H), 2.02 (s, 3H),1.48 (s, 9H); MS (ESI⁺): m/z 362.22 (M+H)⁺.

D) N-(4-(4-Amino-2-fluorophenoxy)pyridin-2-yl)acetamide

A solution of tert-butyl4-(2-acetamidopyridin-4-yloxy)-3-fluorophenylcarbamate (110 mg, 0.30mmol) in 4 M HCl/1,4-dioxane (1.5 mL) was stirred at 0° C. for 20 minthen at room temperature for 25 min. The mixture was diluted with EtOAc(25 mL) and saturated aq. NaHCO₃ solution (20 mL), and stirredvigorously for 5 min. The EtOAc phase was washed with brine, dried(MgSO₄) and concentrated in vacuo to give the title compound (69 mg,87%) as a yellow solid. ¹H NMR (DMSO-d₆) δ 10.49 (s, 1H), 8.13 (d, 1H,J=5.6 Hz), 7.60 (m, 1H), 6.95 (dd, 1H, J=8.6, 9.2 Hz), 6.60 (dd, 1H,J=2.5, 5.6 Hz), 6.48 (dd, 1H, J=2.5, 13.2 Hz), 6.40 (dd, 1H, J=2.0, 8.6Hz), 5.44 (s, 2H), 2.02 (s, 3H).

E)1-(4-(2-Acetamidopyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,hydrochloride salt

A solution of N-(4-(4-amino-2-fluorophenoxy)pyridin-2-yl)acetamide (20mg, 0.077 mmol) in THF (1 mL) was treated with 0.3 M solution of2-(4-fluorophenyl)acetyl isocyanate in toluene (Compound D of Example11, 0.26 mL, 0.77 mmol) and the mixture was stirred at room temperaturefor 1 h. The mixture was concentrated under vacuum and the residuepurified by preparative HPLC (Column A) to give the title compound as aTFA salt. The TFA salt was dissolved in anhydrous MeOH and treated with1 M HCl/Et₂O at 0° C. and stirred for 5 min. The mixture was thenconcentrated in vacuo to give the title compound (12 mg, 33%) as a whitesolid. ¹H NMR (DMSO-d₆): δ 11.04 (s, 1H), 10.65 (s, 1H), 10.58 (s, 1H),8.18 (d, 1H, J=6.1 Hz), 7.77 (dd, 1H, J=2.0, 12.7 Hz), 7.56 (m, 1H),7.40-7.30 (m, 5H), 7.18-7.14 (m, 2H), 6.71 (dd, 1H, J=2.5, 6.1 Hz), 3.74(s, 2H), 2.03 (s, 3H); MS (ESI⁺): m/z 441.18 (M+H)⁺.

Example 81

N-(4-(2-Acetamidopyridin-4-yloxy)-3-fluorophenyl)-2,6-difluorobenzamide,hydrochloride salt

A solution of N-(4-(4-amino-2-fluorophenoxy)pyridin-2-yl)acetamide(Compound B′ of Example 24, 15 mg, 0.057 mmol) in THF (0.5 mL) wastreated with DIPEA (15 μL, 0.086 mmol) and 2-6-difluorobenzoyl chloride(10 mg, 0.057 mmol) and the mixture stirred at room temperature for 1.5h. The mixture was concentrated under vacuum and the residue purified bypreparative HPLC (Column A) to give the title compound as a TFA salt.The TFA salt was dissolved in anhydrous MeOH and treated with 1 MHCl/Et₂O at 0° C. and stirred for 5 min. The mixture was thenconcentrated in vacuo to give the title compound (15 mg, 60%) as aoff-white solid. ¹H NMR (DMSO-d₆) δ 11.17 (s, 1H), 10.79 (s, 1H), 8.21(d, 1H, J=6.1 Hz), 7.89 (dd, 1H, J=2.0, 12.7 Hz), 7.66-7.59 (m, 1H),7.53-7.50 (m, 2H), 7.42 (dd, 1H, J=8.6, 9.2 Hz), 7.28 (dd, 2H, J=8.1,8.1 Hz), 6.80 (dd, 1H, J=2.0, 6.1 Hz), 2.06 (s, 3H); MS (ESI⁺): m/z402.13 (M+H)⁺.

Example 82

1-(3-Fluoro-4-(2-(2-morpholinoethylamino)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea,dihydrochloride salt

A) N-(4-(2-Chloropyridin-4-yloxy)-3-fluorophenyl)acetamide

A mixture of N-(3-fluoro-4-hydroxyphenyl)acetamide (Compound A ofExample 13, 1.33 g, 7.87 mmol), 2-chloro-4-nitropyridine (Aldrich, 1.24g, 7.87 mmol), K₂CO₃ (1.6 g, 11.8 mmol), and DMF (25 mL) was heated at100° C. for 9 h. The mixture was concentrated in vacuo and the residuewas partitioned between EtOAc and saturated aq. NaHCO₃ solution. TheEtOAc phase was washed with brine, dried (MgSO₄), and concentrated invacuo. The residue was purified by flash column chromatography on SiO₂eluting with 30-80% EtOAc in hexanes to give the title compound (1.6 g,73%) as a pale yellow solid. ¹H NMR (DMSO-d₆) δ 10.25 (s, 1H), 8.35 (d,1H, J=7 Hz), 7.80 (d, 1H, J=14 Hz), 7.50 (d, 1H, J=3 Hz), 7.33 (m, 2H),7.02 (m, 1H), 2.06 (s, 3H); MS (ESI⁺): m/z 281.16 (M+H)⁺.

B) N-(4-(2-Chloropyridin-4-yloxy-1-oxide)-3-fluorophenyl)acetamide

A mixture of N-(4-(2-chloropyridin-4-yloxy)-3-fluorophenyl)acetamide(0.98 g, 3.5 mmol), >90%, m-chloroperoxybenzoic acid (1.3 g, 7.6 mmol),and CHCl₃ (50 mL) was stirred at rt for 60 h. The mixture wasconcentrated in vacuo and the residue triturated with Et₂O (2×100 mL) togive the title compound (0.89 g, 86%) as a pale yellow solid. ¹H NMR(DMSO-d₆) δ 10.25 (s, 1H), 8.35 (d, 1H, J=7.3 Hz), 7.80 (d, 1H, J=13Hz), 7.33-7.32 (m, 3H), 7.02 (dd, 1H, J=3.5, 7.5 Hz), 2.06 (s, 3H); MS(ESI⁻): m/z 295.04 (M+H)⁺.

C)N-(3-Fluoro-4-(2-(2-morpholinoethylamino)pyridin-4-yloxy-1-oxide)phenyl)acetamide

A mixture ofN-(4-(2-chloropyridin-4-yloxy-1-oxide)-3-fluorophenyl)acetamidehydrochloride (205 mg, 0.62 mmol), 4-(2-aminoethyl)morpholine (Aldrich,169 mg, 1.30 mmol), and absolute EtOH was heated at reflux 16 h. Thereaction mixture was concentrated in vacuo, and the residue was treatedwith H₂O (3 mL) and applied to a 10 g Varian C-18 cartridge. Thecartridge was eluted first with H₂O then with 30% MeOH in H₂O. Theeluent which contained the desired product was pooled, concentrated to 5mL volume, and extracted 3 times with EtOAc. The combined extracts werewashed with brine, dried (MgSO₄) and concentrated in vacuo to give thetitle compound (100 mg, 40%). ¹H NMR (DMSO-d₆) δ 10.22 (s, 1H), 7.84 (d,1H, J=6 Hz), 7.77 (dd, 1H, J=2, 12 Hz), 7.31 (dd, 1H, J=2, 9 Hz), 7.24(dd, 1H, J=9, 9 Hz), 6.41 (m, 1H), 6.13 (dd, 1H, J=2, 6 Hz), 5.81 (d,1H, J=2.5 Hz), 3.56-3.48 (m, 2H), 3.31-3.19 (m, 4H), 2.38 (t, 2H, J=7Hz), 2.40-2.28 (m, 4H), 2.06 (s, 3H); MS (ESI⁺): m/z 405.22 (M+H)⁺.

D)N-(3-Fluoro-4-(2-(2-morpholinoethylamino)pyridin-4-yloxy)phenyl)acetamide,trifluoroacetic acid salt

A mixture ofN-(3-fluoro-4-(2-(2-morpholinoethylamino)pyridin-4-yloxy-1-oxide)phenyl)acetamide(100 mg, 0.26 mmol), and triphenylphosphine polymer supported (1.4-2.0mmol/g) on polystyrene (500 mg) and DMF (2 mL) was stirred at 135° C.for 15 h. The mixture was filtered to remove the resin and the resinwashed with DMF and EtOAc. The filtrate and washings were combined andconcentrated. The crude product was purified by preparative HPLC (ColumnA) to give the title compound (45 mg, 24%) as a white solid. ¹H NMR(DMSO-d₆) δ 10.33 (s, 1H), 8.02 (d, 1H, J=7 Hz) 7.84 (dd, 1H, J=2, 13Hz), 7.39-7.31 (m, 2H), 6.52 (s, 1H), 6.10 (s, 1H), 3.83 (s, 4H),3.60-3.48 (m, 2H), 3.32-3.18 (m, 6H), 2.08 (s, 3H); MS (ESI⁺): m/z375.12 (M+H)⁺.

E) 4-(4-Amino-2-fluorophenoxy)-N-(2-morpholinoethyl)pyridin-2-amine,hydrochloride salt

A mixture ofN-(3-fluoro-4-(2-(2-morpholinoethylamino)pyridin-4-yloxy)phenyl)acetamidetrifluoroacetate (40 mg), MeOH (1 mL), and 6 M HCl (0.2 mL) was heatedat reflux for 3 h. The mixture was concentrated on a rotary evaporatorand the residue was lyophilized to give the title compound (30 mg) as awhite solid. ¹H NMR (DMSO-d₆) δ 11.12 (s, 1H), 8.85 (s, 1H), 7.95 (d,1H, J=7 Hz), 7.08 (dd, 1H, J=9, 9 Hz), 6.65-6.63 (m, 2H), 6.54 (d, 1H,J=8 Hz), 6.31 (s, 1H), 3.90-3.75 (m 6H), 3.37-3.21 (m, 6H); MS (ESI⁻):m/z 373.14 (M+H)⁺.

F)1-(3-Fluoro-4-(2-(2-morpholinoethylamino)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea,dihydrochloride salt

A solution of4-(4-amino-2-fluorophenoxy)-N-(2-morpholinoethyl)pyridin-2-aminehydrochloride (15 mg, 0.045 mmol) in MeOH (5 mL) was treated with Et₃N(2 mL) and the mixture stirred at room temperature for 5 min. Themixture was concentrated in vacuo to remove the MeOH, the residuesuspended in THF (1 mL) and treated with a solution of 0.3 M solution of2-(4-fluorophenyl)acetyl isocyanate in toluene (Compound D of Example11, 180 mL, 0.054 mmol). After stirring, the mixture was concentrated invacuo and the residue partitioned between EtOAc and saturated NaHCO₃.The EtOAc phase was separated, washed with brine, dried (MgSO₄) andconcentrated. The mixture was concentrated under vacuum and the residuepurified by preparative HPLC (Column A) to give the title compound as aTFA salt. The TFA salt was dissolved in anhydrous MeOH and treated with1 N HCl/Et₂O at 0° C. and stirred for 5 min. The mixture was thenconcentrated in vacuo to give the title compound (10 mg, 43%) as a whitesolid. ¹H NMR (DMSO-d₆) δ 11.05 (s, 1H), 10.61 (s, 1H), 7.98 (d, 1H,J=7.1 Hz), 7.86-7.73 (m, 1H), 7.48-7.38 (m, 1H), 7.37-7.30 (m, 3H),7.24-7.04 (m, 2H), 6.60 (s, 1H), 6.26 (s, 1H), 3.98-3.60 (m, 8H), 3.74(s, 2H), 3.39-3.19 (m, 4H); MS (ESI⁺): m/z 512.2 (M+H)⁺.

Examples 83-85 were prepared in a similar manner as described forExample 82.

Example 83

1-(3-Fluoro-4-(2-(3-morpholinopropylamino)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea,hydrochloride salt

¹H NMR (DMSO-d₆) δ 11.06 (s, 1H), 10.62 (s, 1H), 7.93 (d, 1H, J=7.1 Hz),7.83 (d, 1H, J=12.7 Hz), 7.45-7.33 (m, 4H), 7.16 (dd, 2H, J=8.6, 9.2Hz), 6.64 (s, 1H), 6.23 (s, 1H), 3.95-3.76 (m, 4H), 3.74 (s, 2H),3.70-3.48 (m, 4H), 3.48-3.35 (m, 2H), 3.20-3.-04 (m, 2H), 2.02-1.93 (m,2H).

Example 84

1-(4-(2-(3-(Dimethylamino)propylamino)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,hydrochloride salt

¹H NMR (DMSO-d₆) δ 11.06 (s, 1H), 10.62 (s, 1H), 10.37 (s, 1H), 7.93 (d,1H, J=7.1 Hz), 7.82 (dd, 1H, J=2.0, 12.7 Hz), 7.45 (dd, 1H, J=2.6, 8.6Hz), 7.40 (d, 1H, J=8.6 Hz), 7.37-7.33 (m, 2H), 7.16 (dd, 2H, J=8.7, 9.1Hz), 6.65 (s, 1H), 6.24 (s, 1H), 3.75 (s, 2H), 3.45-3.36 (m, 2H),3.13-3.03 (m, 2H), 2.73 (s, 3H), 2.72 (s, 3H), 1.94-1.90 (m, 2H).

Example 85

1-(4-(2-(4-(Dimethylamino)butylamino)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,hydrochloride salt

MS (ESI⁺): m/z 498.2 (M+H)⁺.

Example 86

1-(4-(2,6-Diaminopyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,hydrochloride salt

A) 4-Chloropyridine-2,6-dicarboxamide

A mixture of chelidamic acid (3.19 g, 17.0 mmol), PCl₅ (2.1 g) and CCl₄(30 mL) was refluxed for 6 h and then cooled to 65° C. and treated withMeOH (5 mL) under gentle reflux. The mixture was refluxed for 5 h andthen concentrated in vacuo. The residue was treated with ice-water (50mL) and the precipitated solid was collected by filtration and suckeddry on the funnel to give white needles of2,6-biscarbomethoxy-4-chloropyridine (2.4 g). The product was treatedwith ˜7 M NH₃/MeOH and stirred at room temperature for 1 h. The mixturewas filtered to collect the title compound as a white solid (1.8 g,53%). ¹H NMR (DMSO-d₆) δ 8.91 (s, 2H), 8.15 (s, 2H), 7.87 (s, 2H).

B) tert-Butyl 4-(2,6-dicarbamoylpyridin-4-yloxy)-3-fluorophenylcarbamate

A solution of N-Boc-4-amino-2-fluorophenol (228 mg, 1.0 mmol) in DMF (2mL) was treated with t-BuOK (124 mg, 1.1 mmol) and the mixture stirredat room temperature for 2 h. The mixture was treated with4-chloropyridine-2,6-dicarboxamide (200 mg, 1.0 mmol) and K₂CO₃ (35 mg,0.5 mmol) and heated at 80° C. for 1.5 h. The mixture was concentratedin vacuo, treated with EtOAc (10 mL) and

H₂O (10 mL) and filtered to remove the insoluble material. The EtOAcphase was washed with brine, dried (MgSO₄) and concentrated in vacuo.Purification of the residue by flash column chromatography on SiO₂eluting with 30-100% EtOAc/hexanes gave the title compound (170 mg, 44%)as a white solid containing 10% of the starting chloropyridine. ¹H NMR(DMSO-d₆) δ 9.77 (s, 1H), 8.86 (s, 2H), 7.87 (s, 1H), 7.63 (d, 1H,J=12.1 Hz), 7.55 (s, 2H), 7.38-7.31 (m, 2H), 1.48 (s, 9H).

C) tert-Butyl 4-(2,6-diaminopyridin-4-yloxy)-3-fluorophenylcarbamate

The title compound was prepared from tert-butyl4-(2,6-dicarbamoylpyridin-4-yloxy)-3-fluorophenylcarbamate (110 mg, 0.28mmol) using a similar procedure as described for Step B of Example 80.Flash chromatography on SiO₂ eluting with 0-2% MeOH/EtOAc gave the titlecompound (60 mg, 63%) as a white solid. ¹H NMR (DMSO-d₆) δ 9.60 (s, 1H),7.50 (dd, 1H, J=1.8, 13.6 Hz), 7.21 (dd, 1H, J=2.2, 8.7 Hz), 7.13 (dd,1H, J=8.7, 9.2 Hz), 5.40 (s, 4H), 5.13 (s, 2H), 1.47 (s, 9H); MS (ESI⁺):m/z 335.23 (M+H)⁺.

D) 4-(4-Amino-2-fluorophenoxy)pyridine-2,6-diamine

The title compound was prepared form tert-butyl4-(2,6-diaminopyridin-4-yloxy)-3-fluorophenylcarbamate (30 mg, 0.089mmol) in a manner similar to that is described in Step D of Example 80to give a clear oil (20 mg, 100%). MS (ESI⁺): m/z 235.22 (M+H)⁺.

E)1-(4-(2,6-Diaminopyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,hydrochloride salt

The title compound was prepared from4-(4-amino-2-fluorophenoxy)pyridine-2,6-diamine (19 mg, 0.081 mmol) anda solution of 2-(4-fluorophenyl)acetyl isocyanate in toluene (0.3 M,Compound D of Example 11, 0.27 mL, 0.081 mmol) in a similar manner asStep D of Example 33. The reaction mixture was purified by preparativeHPLC (Column A) to give the title compound as a TFA salt. The TFA saltwas dissolved in anhydrous MeOH and treated with 1 M HCl/Et₂O at 0° C.and stirred for 5 min. The mixture was then concentrated in vacuo togive the title compound (8 mg, 24%) as a pale yellow solid. ¹H NMR(DMSO-d₆) δ 11.01 (s, 1H), 10.51 (s, 1H), 7.68 (dd, 1H, J=2.6, 12.7 Hz),7.36-7.30 (m, 3H), 7.22-7.14 (m, 3H), 5.52 (s, 4H), 5.15 (s, 2H), 3.73(s, 2H); MS (ESI⁺): m/z 414.09 (M+H)⁺.

Example 87

1-(4-((2-(3-(Dimethylamino)propylamino)pyridin-4-yl)methyl)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,dihydrochloride salt

A) tert-Butyl 4-bromo-3-fluorophenylcarbamate

To a solution of 4-bromo-3-fluorobenzenamine (Lancaster, 7.05 g, 37.1mmol) in anhydrous tetrahydrofuran (40 mL) at room temperature was added(Boc)₂O (8.10 g, 37.1 mmol) and triethylamine (5.17 mL, 37.1 mmol). Thereaction mixture was heated at reflux overnight. After cooling down, thereaction mixture was concentrated under reduced pressure. The residuewas purified by flash column chromatography on SiO₂ eluting with 20%dichloromethane in hexane, then 20% ethyl acetate in hexane to givetert-butyl 4-bromo-3-fluorophenylcarbamate (5.30 g, 49% yield). MS(ESI⁺): m/z 290.2 (M+H)⁺.

B) tert-Butyl4-((2-chloropyridin-4-yl)(hydroxy)methyl)-3-fluorophenylcarbamate

To a solution of tert-butyl 4-bromo-3-fluorophenylcarbamate (2.60 g, 9.0mmol) in anhydrous THF (30 mL) at −78° C. was added MeMgBr (3.0 M inEt₂O, 3.1 mL, 9.3 mmol) via syringe. The solution was stirred for 10 minat that temperature, and then warmed to 0° C. for 0.5 h. After thesolution was cooled back to −78° C., a solution of t-BuLi (1.7 M inhexane, 10.6 mL, 18.1 mmol) was added over 4 min. The resulting solutionwas allowed to stir for 5 min before a solution of2-chloroisonicotinaldehyde (1.41 g, 10 mmol) (for preparation, see Frey,L. F. et al. Tetrahedron Lett. 2001, 42, 6815) in anhydrous THF (25 mL)was added in 3 min. The reaction mixture was stirred at −78° C. for 20min and 2.0 mL of MeOH was added. The solution was then concentratedunder reduced pressure and the residue was dissolved in 200 mL of EtOAc.It was subsequently washed with H₂O (2×50 mL), brine (2×50 mL) and driedover MgSO₄. After filtration and concentration, the residue was purifiedby flash chromatography on SiO₂ eluting with 0%-50% EtOAc in hexane togive tert-butyl4-((2-chloropyridin-4-yl)(hydroxy)methyl)-3-fluorophenylcarbamate (1.30g, 41% yield). MS (ESI⁺): m/z 353.28/355.24 (M+H)⁺.

C) tert-Butyl4-((2-chloropyridin-N-oxide-4-yl)(hydroxy)methyl)-3-fluorophenylcarbamate

To a solution of tert-butyl4-((2-chloropyridin-4-yl)(hydroxy)methyl)-3-fluorophenylcarbamate (1.20g, 3.40 mmol) in a mixture of dichloromethane (100 mL) and ethyl acetate(10 mL) was added m-CPBA (70%, 2.34 g, 9.48 mmol). The reaction mixturewas stirred at room temperature for 2 h, and then heated at reflux for 5h. The solvent was removed under reduced pressure and the residue waspurified by flash chromatography on SiO₂ eluting with 50% EtOAc inhexane, 100% EtOAc and then 10% MeOH in EtOAc, to give tert-butyl4-((2-chloropyridin-N-oxide-4-yl)(hydroxy)methyl)-3-fluorophenylcarbamate(840 mg, 67% yield). MS (ESI⁺): m/z 369.13/371.13 (M+H)⁺.

D) tert-Butyl4-((2-(3-(dimethylamino)propylamino)pyridine-4-yl)(hydroxy)methyl)-3-fluorophenylcarbamate

To a solution of tert-butyl4-((2-chloropyridin-N-oxide-4-yl)(hydroxy)methyl)-3-fluorophenylcarbamate(80 mg, 0.22 mmol) in EtOH (2.0 mL) was addedN¹,N¹-dimethylpropane-1,3-diamine (225 mg, 2.2 mmol). The reactionmixture was heated at 80° C. for 12 h and the solvent was removed toprovide crude tert-butyl4-((2-(3-(dimethylamino)propylamino)pyridine-N-oxide-4-yl)(hydroxy)methyl)-3-fluorophenylcarbamate,which was directly used in the next step. MS (ESI⁺): m/z 435.37 (M+H)⁺.

To a solution of tert-butyl4-((2-(3-(dimethylamino)propylamino)pyridine-N-oxide-4-yl)(hydroxy)methyl)-3-fluorophenylcarbamate(˜0.22 mmol) in MeOH (2.0 mL) was added zinc (114 mg, 1.75 mmol) andNH₄CO₂H (139 mg, 2.20 mmol). The suspension was refluxed overnight. Morezinc (114 mg) and NH₄CO₂H (139 mg) were added and the suspension wasrefluxed for 2 h. After cooling down, the solution was filtered and thefiltrate was concentrated under reduced pressure. The residue was thenpurified by flash chromatography on SiO₂ eluting with 10-30% MeOH in DCMto give tert-butyl4-((2-(3-(dimethylamino)propylamino)pyridine-4-yl)(hydroxy)methyl)-3-fluorophenylcarbamate(80 mg, 87% yield). MS (ESI⁺): m/z 419.34 (M+H)⁺.

E) 4-(4-Amino-2-fluorobenzyl)-N-(3-(dimethylamino)propyl)pyridin-2-amine

To a solution of tert-butyl4-((2-(3-(dimethylamino)propylamino)pyridine-4-yl)(hydroxy)methyl)-3-fluorophenylcarbamate(80 mg, 0.19 mmol) in MeOH (5.0 mL) was added 2 mL of conc. HCl andpalladium on charcoal (10%, 200 mg). The suspension was heated at 75° C.under H₂ atmosphere for 24 h. The mixture was cooled down, filtered andconcentrated in vacuo. The residue was dissolved in 1 mL of conc. NH₄OHand it was extracted with DCM (5×5 mL). The combined organic layer wasdried over Na₂SO₄. After filtration, it was concentrated in vacuo togive4-(4-amino-2-fluorobenzyl)-N-(3-(dimethylamino)propyl)pyridin-2-amine(31 mg, 40% yield). MS (ESI⁺): m/z 303.31 (M+H)⁺.

F)1-(4-((2-(3-(Dimethylamino)propylamino)pyridin-4-yl)methyl)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,dihydrochloride salt

To a solution of4-(4-amino-2-fluorobenzyl)-N-(3-(dimethylamino)propyl)pyridin-2-amine(30 mg, 0.1 mmol) in DCM (2 mL) was added a solution of2-(4-fluorophenyl)acetyl isocyanate (Compound D of Example 11, 0.347 Min toluene, 0.25 mL). The mixture was stirred at room temperature for0.5 h before it was quenched with MeOH. The solution was concentrated invacuo and the residue was purified by prep. HPLC. The desired fractionswere collected and concentrated in vacuo. The residue was dissolved inMeOH and polymer bound diethylene triamine (50 mg) was added to removetrifluoroacetic acid. After filtration and concentration, the residuewas converted to a hydrochloride salt by the addition of 1 N HCl (0.5mL) and lyophilized to give1-(4-((2-(3-(dimethylamino)propylamino)pyridin-4-yl)methyl)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)ureahydrochloride (8.0 mg, 14% yield). MS (ESI⁺): m/z 482.24 (M+H)⁺.

Example 88

1-(4-((2-(3-(Dimethylamino)propylamino)pyridin-4-yl)(hydroxy)methyl)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea

A) tert-Butyl 4-((2-chloropyridin-4-yl)(hydroxy)methyl)phenylcarbamate

Prepared in a manner similar to that which is described in Step B ofExample 87. 2-Chloroisonicotinaldehyde (141 mg, 1.0 mmol) was convertedto tert-butyl 4-((2-chloropyridin-4-yl)(hydroxy)methyl)phenylcarbamate(190 mg, 57% yield). MS (ESI⁺): m/z 335.27/337.27 (M+H)⁺.

B) tert-Butyl4-((2-chloropyridin-N-oxide-4-yl)(hydroxy)methyl)phenylcarbamate

Prepared in a manner similar to that which is described in Step C ofExample 87. tert-Butyl4-((2-chloropyridin-4-yl)(hydroxy)methyl)phenylcarbamate (78 mg, 0.23mmol) was converted to tert-butyl4-((2-chloropyridin-N-oxide-4-yl)(hydroxy)methyl)phenylcarbamate (36 mg,44% yield). MS (ESI⁺): m/z 351.28/353.27 (M+H)⁺.

C) tert-Butyl4-((2-(3-(dimethylamino)propylamino)pyridin-4-yl)(hydroxy)methyl)phenylcarbamate

Prepared in a manner similar to that which is described in Step D ofExample 87. tert-Butyl4-((2-chloropyridin-N-oxide-4-yl)(hydroxy)methyl)phenylcarbamate (36 mg,0.1 mmol) was converted to tert-butyl4-((2-(3-(dimethylamino)propylamino)pyridin-4-yl)(hydroxy)methyl)phenylcarbamate(16 mg, 40% yield). MS (ESI⁺): m/z 401.38 (M+H)⁺.

D) (4-Aminophenyl)(2-(3-(dimethylamino)propylamino)pyridin-4-yl)methanol

To a solution of tert-butyl4-((2-(3-(dimethylamino)propylamino)pyridin-4-yl)(hydroxy)methyl)phenylcarbamate(16 mg, 0.04 mmol) in 1 mL of DCM were added Et₃SiH (0.1 mL)/TFA in DCM(10%, 0.2 mL). The mixture was stirred for ½ hr and no reaction wasdetected by LC-MS. Another 0.1 mL of Et₃SiH and 0.8 mL of TFA in DCM(10%) were added and the mixture was stirred for 2 h. The solvent wasremoved and was purified by solid extraction (Waters Oasis MCXextraction cartridge) to give(4-aminophenyl)(2-(3-(dimethylamino)propylamino)pyridin-4-yl)methanol(6.0 mg, 50% yield). MS (ESI⁺): m/z 301.40 (M+H)⁺.

E)1-(4-((2-(3-(Dimethylamino)propylamino)pyridin-4-yl)(hydroxy)methyl)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea

Prepared in a manner similar to that which is described in Step F ofExample 87.4-Aminophenyl-(2-(3-(dimethylamino)propylamino)pyridin-4-yl)methanol(6.0 mg, 0.02 mmol) was converted to1-(4-((2-(3-(dimethylamino)propylamino)pyridin-4-yl)(hydroxy)methyl)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea,bis-trifluoroacetic acid (6.1 mg, 43% yield). ¹H NMR (CD₃OD) δ 7.82 (d,1H, J=6.4 Hz), 7.50 (m, 2H), 7.36 (m, 4H), 7.07 (m, 3H), 6.75 (m, 1H),5.68 (s, 1H), 3.71 (s, 2H), 3.21-3.49 (m, 4H), 2.90 (s, 6H), 2.08 (m,2H); MS (ESI⁺): m/z 480.31 (M+H)⁺.

Example 89

1-(4-((2-Aminopyridin-4-yl)methyl)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,trifluoroacetic acid salt

A) tert-Butyl4-((2-(allylamino)pyridin-N-oxide-4-yl)(hydroxy)methyl)-3-fluorophenylcarbamate

To a solution of tert-butyl4-((2-chloropyridin-N-oxide-4-yl)(hydroxy)methyl)-3-fluorophenylcarbamate(Step C of Example 87, 500 mg, 1.36 mmol) in EtOH (14 mL) was addedallylamine (1.0 mL, 13.6 mmol). The mixture was heated at 80° C.overnight. After cooling down, the solvent was removed and the residuewas purified by flash chromatography on SiO₂ eluting with 0%-15% MeOH inDCM to give tert-butyl4-((2-(allylamino)pyridin-N-oxide-4-yl)(hydroxy)methyl)-3-fluorophenylcarbamate(440 mg, 83% yield). MS (ESI⁺): m/z 390.19 (M+H)⁺.

B) tert-Butyl4-((2-(allylamino)pyridin-4-yl)(hydroxy)methyl)-3-fluorophenylcarbamate

Prepared in a manner similar to that which is described in Step D ofExample 87. tert-Butyl4-((2-(allylamino)pyridin-N-oxide-4-yl)(hydroxy)methyl)-3-fluorophenylcarbamate(440 mg, 1.13 mmol) was converted to tert-butyl4-((2-(allylamino)pyridin-4-yl)(hydroxy)methyl)-3-fluorophenylcarbamate(400 mg, 95% yield). MS (ESI⁺): m/z 374.33 (M+H)⁺.

C)(2-(Allylamino)pyridin-4-yl)(4-(tert-butoxycarbonyl)-2-fluorophenyl)methylacetate

To a solution of tert-butyl4-((2-(allylamino)pyridin-4-yl)(hydroxy)methyl)-3-fluorophenylcarbamate(400 mg, 1.1 mmol) in THF (10 mL) were added diisopropylethylamine(DIEA) (0.2 mL, 1.1 mmol), 4-dimethylaminopyridine (DMAP) (360 mg, 3.0mmol) and Ac₂O (0.29 mL, 3.0 mmol). The mixture was stirred overnightand then heated at reflux for 1 h. After cooling down, the solvent wasremoved under reduced pressure and the residue was purified by flashchromatography on SiO₂ eluting with 0%-100% EtOAc in hexane to give(2-(allylamino)pyridin-4-yl)(4-(tert-butoxycarbonyl)-2-fluorophenyl)methylacetate (390 mg, 85% yield). MS (ESI⁺): m/z 416.33 (M+H)⁺.

D) (2-Aminopyridin-4-yl)(4-(tert-butoxycarbonyl)-2-fluorophenyl)methylacetate

A solution of(2-(allylamino)pyridin-4-yl)(4-(tert-butoxycarbonyl)-2-fluorophenyl)methylacetate (380 mg, 0.91 mmol) in a mixture of EtOH/H₂O (10:1, 40 mL) wasdegassed via bubbling N₂ into the solution for 1 h. To the mixture wasadded Rh(PPh₃)₃Cl (80 mg, 0.09 mmol). The solution was refluxed toremove the solvent and the residue was purified by flash chromatographyon SiO₂, followed by preparative HPLC purification, to give(2-aminopyridin-4-yl)(4-(tert-butoxycarbonyl)-2-fluorophenyl)methylacetate, trifluoroacetic acid salt (185 mg, 42% yield). MS (ESI⁺): m/z376.26 (M+H)⁺.

E) tert-Butyl 4-((2-aminopyridin-4-yl)methyl)-3-fluorophenylcarbamate

To a solution of(2-aminopyridin-4-yl)(4-(tert-butoxycarbonyl)-2-fluorophenyl)methylacetate as a TFA salt (180 mg, 0.37 mmol) in MeOH (10 mL) was added 10%Pd/C (90 mg). The suspension was stirred under H₂ atmosphere for 1 h.The catalyst was removed and the filtrate was concentrated in vacuo. Theresidue was then purified by flash chromatography on SiO₂ eluting with3% MeOH in DCM, to give tert-butyl4-((2-aminopyridin-4-yl)methyl)-3-fluorophenylcarbamate as a TFA salt(73 mg, 46% yield). MS (ESI⁺): m/z 318.24 (M+H)⁺.

F) 4-(4-Amino-2-fluorobenzyl)pyridin-2-amine

To a solution of tert-butyl4-((2-aminopyridin-4-yl)methyl)-3-fluorophenylcarbamate as a TFA salt(73 mg, 0.17 mmol) in DCM (4.0 mL) was added TFA (1.0 mL). The solutionwas stirred at room temperature for 2 h and the solvent was removed invacuo to give 4-(4-amino-2-fluorobenzyl)pyridin-2-amine,bis-trifluoroacetic acid (70 mg, 93% yield). MS (ESI⁺): m/z 218.12(M+H)⁺.

G)1-(4-((2-Aminopyridin-4-yl)methyl)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,trifluoroacetic acid salt

Prepared in a manner similar to that which is described in Step F ofExample 87. 4-(4-Amino-2-fluorobenzyl)pyridin-2-amine as 2 TFA salt (19mg, 0.042 mmol) was converted to1-(4-((2-aminopyridin-4-yl)methyl)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,trifluoroacetic acid salt (19 mg, 88% yield). ¹H NMR (DMSO-d₆) δ 10.94(s, 1H), 10.47 (s, 1H), 7.76 (m, 3H), 7.50 (d, 1H, J=11.5 Hz), 7.10-7.26(m, 4H), 7.10 (m, 2H), 6.65 (d, 1H, J=6.5 Hz), 6.55 (s, 1H), 3.89 (s,2H), 3.65 (s, 2H); MS (ESI⁺): m/z 397.26 (M+H)⁺.

Example 90

1-(4-(2-Carbamoylpyridin-4-yloxy)-3-chlorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea

A) 4-(4-Amino-2-chlorophenoxy)picolinamide

To a solution of 4-amino-2-chlorophenol (Aldrich, 430 mg, 3.0 mmol) inDMF (2.0 mL) at room temperature was added KOt-Bu (352 mg, 3.2 mmol).The mixture was allowed to stir at room temperature for 1 h. To thesolution were then added 4-chloropicolinamide (468 mg, 3.0 mmol) andK₂CO₃ (221 mg, 1.6 mmol). The resulting suspension was heated at 90° C.overnight. After cooling down, the suspension was diluted with 100 mL ofEtOAc and 50 mL of H₂O. The organic layer was separated and washed withbrine (2×25 mL) and dried over MgSO₄. After filtration andconcentration, the solid was triturated with 50 mL of DCM. The solid wasthen collected and washed with DCM (2×20 mL), EtOAc (5.0 mL) and driedto give 4-(4-amino-2-chlorophenoxy)picolinamide (320 mg, 40% yield). MS(ESI⁺): m/z 264.12/266.07 (M+H)⁺.

B)1-(4-(2-Carbamoylpyridin-4-yloxy)-3-chlorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea

Prepared in a manner similar to that which is described in Step F ofExample 87. 4-(4-Amino-2-chlorophenoxy)picolinamide (79 mg, 0.30 mmol)in DMF (1.0 mL) was converted to1-(4-(2-carbamoylpyridin-4-yloxy)-3-chlorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea(65 mg, 49% yield). ¹H NMR (DMSO-d₆) δ 11.05 (s, 1H), 10.58 (s, 1H),8.52 (d, 1H, J=4.5 Hz), 8.15 (s, 1H), 7.98 (s, 1H), 7.70 (s, 1H), 7.55(m, 1H), 7.39 (m, 3H), 7.27 (m, 1H), 7.16 (m, 3H), 3.73 (s, 2H); MS(ESI⁺): m/z 443.17 (M+H)⁺.

Example 91

1-(4-(2-Aminopyridin-4-yloxy)-3-chlorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,hydrochloride salt

To a solution of1-(4-(2-carbamoylpyridin-4-yloxy)-3-chlorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea(Example 90, 27 mg, 0.06 mmol) in DMF (1.0 mL) were added H₂O (2.2 mg,0.12 mmol), pyridine (0.04 mL) and bis(trifluoroacetoxy)iodobenzene(Aldrich, 39 mg, 0.09 mmol) at room temperature. The solution wasallowed to stir overnight and then it was purified on prep HPLC to givethe desired product, which was further converted to1-(4-(2-aminopyridin-4-yloxy)-3-chlorophenyl)-3-(2-(4-fluorophenyl)acetyl)ureahydrochloride (19 mg, 70% yield) by the addition of 1N HCl solution (0.5mL). ¹H NMR (DMSO-d₆) δ 13.50 (s, 1H), 11.02 (s, 1H), 10.57 (s, 1H),7.80-7.95 (m, 4H), 7.55 (m, 1H), 7.37 (m, 1H), 7.30 (m, 2H), 7.11 (m,2H), 6.60 (m, 1H), 6.00 (s, 1H), 3.70 (s, 2H); MS (ESI⁺): m/z 415.16(M+H)⁺.

Example 92

1-(4-(2-Aminopyridin-4-yloxy)-2-chlorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea

A)1-(4-(2-Carbamoylpyridin-4-yloxy)-2-chlorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea

Prepared in a manner similar to that which is described in Step A ofExample 90. 4-(4-Amino-3-chlorophenoxy)picolinamide (39 mg, 0.19 mmol)in DMF (1.0 mL) was converted to1-(4-(2-carbamoylpyridin-4-yloxy)-2-chlorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea(18 mg, 41% yield) after prep HPLC purification. MS (ESI⁺): m/z443.13/445.14 (M+H)⁺.

B)1-(4-(2-Aminopyridin-4-yloxy)-2-chlorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea

Prepared in a manner similar to that which is described for Example 91.1-(4-(2-Carbamoylpyridin-4-yloxy)-2-chlorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea(18 mg, 0.04 mmol) in DMF (1.0 mL) was converted to1-(4-(2-aminopyridin-4-yloxy)-2-chlorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea(10 mg, 55% yield). ¹H NMR (DMSO-d₆) δ 13.47 (s, 1H), 11.26 (s, 1H),11.08 (s, 1H), 8.37 (d, 1H, J=8.5 Hz), 7.95 (d, 1H, J=7.5 Hz), 7.88 (s,2H), 7.62 (s, 1H), 7.35 (m, 3H), 7.17 (m, 2H), 6.64 (d, 1H, J=7.5 Hz),6.13 (s, 1H), 3.76 (s, 2H); MS (ESI⁺): m/z 415.18/417.17 (M+H)⁺.

Example 93

1-(4-(2-Carbamoylpyridin-4-yloxy)-3-methylphenyl)-3-(2-(4-fluorophenyl)acetyl)urea

A) 4-(4-Amino-2-methylphenoxy)picolinamide

Prepared in a manner similar to that which is described in Step A ofExample 90. 4-Amino-2-methylphenol (246 mg, 2.0 mmol) was converted to4-(4-amino-2-methylphenoxy)picolinamide (230 mg, 47% yield). MS (ESI⁺):m/z 244.15 (M+H)⁺.

B)1-(4-(2-Carbamoylpyridin-4-yloxy)-3-methylphenyl)-3-(2-(4-fluorophenyl)acetyl)urea

Prepared in a manner similar to that which is described in Step F ofExample 87. 4-(4-Amino-2-methylphenoxy)picolinamide (48 mg, 0.2 mmol) inDMF (1.0 mL) was converted to1-(4-(2-carbamoylpyridin-4-yloxy)-3-methylphenyl)-3-(2-(4-fluorophenyl)acetyl)urea(35 mg, 41% yield. ¹H NMR (DMSO-d₆) δ 10.92 (s, 1H), 10.44 (s, 1H), 8.44(d, 1H, J=5.5 Hz), 8.06 (s, 1H), 7.63 (s, 1H), 7.50 (s, 1H), 7.42 (m,1H), 7.31 (m, 2H), 7.24 (d, 1H, J=2.0 Hz), 7.06-7.12 (m, 4H), 3.69 (s,2H), 2.02 (s, 3H);). MS (ESI⁺): m/z 423.17 (M+H)⁺.

Example 94

1-(4-(2-Aminopyridin-4-yloxy)-3-methylphenyl)-3-(2-(4-fluorophenyl)acetyl)urea,hydrochloride salt

Prepared in a manner similar to that which is described in Step A ofExample 91.1-(4-(2-Carbamoylpyridin-4-yloxy)-3-methylphenyl)-3-(2-(4-fluorophenyl)acetyl)urea(27 mg, 0.06 mmol) in DMF (1.0 mL) was converted to1-(4-(2-aminopyridin-4-yloxy)-3-methylphenyl)-3-(2-(4-fluorophenyl)acetyl)urea,hydrochloride salt (24 mg, 88% yield) after HPLC purification. ¹H NMR(DMSO-d₆) δ 13.18 (s, 1H), 10.93 (s, 1H), 10.45 (s, 1H), 7.88 (d, 1H,J=7.0 Hz), 7.73 (s, 2H), 7.50 (m, 2H), 7.29 (m, 2H), 7.10 (m, 3H), 6.56(d, 1H, J=7.0 Hz), 5.91 (d, 1H, J=2.5 Hz), 3.68 (s, 2H), 2.02 (s, 3H);MS (ESI⁺): m/z 395.20 (M+H)⁺.

Example 95

1-(4-(2-Aminopyridin-4-yloxy)-2-(trifluoromethyl)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea,hydrochloride salt

A) 4-Amino-3-(trifluoromethyl)phenol

A solution of 4-nitro-3-(trifluoromethyl)phenol (Aldrich, 414 mg, 2.0mmol) in 10 mL of MeOH was added 10% Pd/C (100 mg). The suspension wasstirred under H₂ atmosphere for 12 h and it was then filtered andconcentrated in vacuo to give 4-amino-3-(trifluoromethyl)phenol (350 mg,95% yield), which was sufficiently pure to use in the next step. MS(ESI⁺): m/z 178.02 (M+H)⁺.

B) 4-(4-Amino-3-(trifluoromethyl)phenoxy)picolinamide

Prepared in a manner similar to that which is described in Step A ofExample 90. 4-Amino-3-(trifluoromethyl)phenol (177 mg, 1.0 mmol) in DMF(2.0 mL) was converted to4-(4-amino-3-(trifluoromethyl)phenoxy)picolinamide (180 mg, 61% yield).MS (ESI⁺): m/z 298.20 (M+H)⁺.

C)1-(4-(2-Carbamoylpyridin-4-yloxy)-2-(trifluoromethyl)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea

Prepared in a manner similar to that which is described in Step F ofExample 87. 4-(4-Amino-3-(trifluoromethyl)phenoxy)picolinamide (30 mg,0.1 mmol) in DMF (1.0 mL) was converted to1-(4-(2-carbamoylpyridin-4-yloxy)-2-(trifluoromethyl)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea(30 mg, 63% yield). MS (ESI⁺): m/z 477.12 (M+H)⁺.

D)1-(4-(2-Aminopyridin-4-yloxy)-2-(trifluoromethyl)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea

Prepared in a manner similar to that which is described in Step A ofExample 91.1-(4-(2-Carbamoylpyridin-4-yloxy)-2-(trifluoromethyl)phenyl)-3-(2-(4fluorophenyl)acetyl)urea (26 mg, 0.055 mmol) in DMF (1.0 mL) wasconverted to1-(4-(2-aminopyridin-4-yloxy)-2-(trifluoromethyl)phenyl)-3-(2-(4-fluorophenyl)acetyl)ureahydrochloride (15 mg, 56% yield) after prep. HPLC purification. ¹H NMR(DMSO-d₆) δ 13.40 (s, 1H), 11.28 (s, 1H), 10.95 (s, 1H), 8.25 (d, 1H,J=8.5 Hz), 7.97 (d, 1H, J=7.0 Hz), 7.88 (s, 2H), 7.72 (d, 1H, J=2.5 Hz),7.65 (m, 1H), 7.35 (m, 2H), 7.19 (m, 2H), 6.66 (d, 1H, J=2.5 Hz), 3.75(s, 2H); MS (ESI⁺): m/z 449.14 (M+H)⁺.

Example 96

1-(4-(2-Aminopyridin-4-yloxy)-2-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,trifluoroacetic acid salt

A) 4-(3-Fluoro-4-pivalamidophenoxy)picolinamide

To a solution of 4-amino-3-fluorophenol (Oakwood Products Inc., 252 mg,2.0 mmol) in NMP (4.0 mL) were added 4-chloropicolinamide (312 mg, 2.0mmol) and DIEA (0.3 mL). The solution was heated at 250° C. in amicrowave oven. After cooling down, the solution was diluted with H₂Oand the solution was extracted with EtOAc (3×40 mL). The combinedorganic layers were washed with brine, dried over MgSO₄. Afterfiltration and concentration, the residue was purified by flashchromatography on SiO₂ eluting with 0-30% MeOH in DCM to give a fractioncontaining 4-(4-amino-3-fluorophenoxy)picolinamide (50% pure, HPLC-UVdetection). MS (ESI⁺): m/z 248.12 (M+H)⁺.

To a solution of 4-(4-amino-3-fluorophenoxy)picolinamide, obtained fromprevious step in THF (3.0 mL) and DCM (10.0 mL) were added 1 N NaOH (5.0mL) and trimethylacetyl chloride (0.25 mL, 2 mmol) at room temperature.The solution was stirred for 2 h and was then extracted with EtOAc. Theorganic layer was washed with brine and dried over MgSO₄. Afterfiltration and concentration, the residue was purified by flashchromatography on SiO₂ eluting with 0%-100% EtOAc in hexane to give4-(3-fluoro-4-pivalamidophenoxy)picolinamide (110 mg, 17% yield for twosteps). MS (ESI⁺): m/z 332.18 (M+H)⁺.

B) N-(4-(2-Aminopyridin-4-yloxy)-2-fluorophenyl)pivalamide

Prepared in a manner similar to that which is described in Step A ofExample 91. 4-(3-Fluoro-4-pivalamidophenoxy)picolinamide (110 mg, 0.33mmol) in acetonitrile (4 mL) was converted toN-(4-(2-aminopyridin-4-yloxy)-2-fluorophenyl)pivalamide (70 mg, 70%yield). MS (ESI⁺): m/z 304.21 (M+H)⁺.

C) 4-(4-Amino-3-fluorophenoxy)pyridin-2-amine

A solution of N-(4-(2-aminopyridin-4-yloxy)-2-fluorophenyl)pivalamide(70 mg, 0.23 mmol) in 3 mL of MeOH was added 2 mL of 6 N HCl. Themixture was then heated at reflux for 48 h. After cooling down, thesolvent was removed under reduced pressure and the residue was purifiedby solid extraction (Waters Oasis MCX extraction cartridge) to give4-(4-amino-3-fluorophenoxy)pyridin-2-amine (27 mg, 54% yield). MS(ESI⁺): m/z 220.21 (M+H)⁺.

D)1-(4-(2-Aminopyridin-4-yloxy)-2-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,trifluoroacetic acid salt

Prepared in a manner similar to that which is described in Step F ofExample 87. 4-(4-Amino-3-fluorophenoxy)pyridin-2-amine (28 mg, 0.095mmol) in THF (2.0 mL) was converted to1-(4-(2-aminopyridin-4-yloxy)-2-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)ureatrifluoroacetic acid (23 mg, 47% yield) after prep. HPLC purification.¹H NMR (DMSO-d₆) δ 11.20 (s, 1H), 10.77 (s, 1H), 8.23 (m, 1H), 7.94 (d,1H, J=6.5 Hz), 7.70 (s, 2H), 7.45 (m, 1H), 7.35 (m, 2H), 7.16 (m, 3H),6.64 (d, 1H, J=2.5 Hz), 6.11 (s, 1H), 3.75 (s, 2H); MS (ESI⁺): m/z399.12 (M+H)⁺.

Example 97

1-(4-(2-Aminopyridin-4-yloxy)-2,3-difluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,trifluoroacetic acid salt

A) 4-Amino-2,3-difluorophenol

To a solution of 1,2,3-trifluoro-4-nitrobenzene (Aldrich, 15.0 g, 84.7mmol) in DMF (25.0 mL) were added K₂CO₃ (17.6 g, 127.8 mmol) andbenzylalcohol (8.8 mL, 85.0 mmol). The suspension was stirred overnight.To the reaction mixture was then added H₂O (100 mL) and the solution waskept at 4° C. overnight. The precipitate was then collected and washedwith H₂O to give a mixture of two isomers (22.4 g)[1-(benzyloxy)-2,3-difluoro-4-nitrobenzene and2-(benzyloxy)-3,4-difluoro-1-nitrobenzene in a ratio of 1:1].

To a solution of [1-(benzyloxy)-2,3-difluoro-4-nitrobenzene and2-(benzyloxy)-3,4-difluoro-1-nitrobenzene] (22.4 g, 84.5 mmol) in EtOAc(20.0 mL) and MeOH (100.0 mL) was added 10% Pd/C (1.0 g). The suspensionwas stirred under H₂ atmosphere for 12 h. The suspension was thenfiltered and concentrated in vacuo to give a mixture of two isomers(12.6 g) [4-amino-2,3-difluorophenol and 6-amino-2,3-difluorophenol in aratio of 1:1]. MS (ESI⁺): m/z 146.00 (M+H)⁺.

B) N-(4-(2-Aminopyridin-4-yloxy)-2,3-difluorophenyl)pivalamide

Prepared in a manner similar to that which is described in Step A ofExample 90. A mixture of 4-amino-2,3-difluorophenol and6-amino-2,3-difluorophenol (580 mg, 4.0 mmol) in DMF (3.0 mL) wasconverted to a mixture of 4-(4-amino-2,3-difluorophenoxy)picolinamideand 4-(6-amino-2,3-difluorophenoxy)picolinamide (300 mg). MS (ESI⁺): m/z266.13 (M+H)⁺.

Prepared in a manner similar to that which is described in Step A ofExample 96. A mixture of 4-(4-amino-2,3-difluorophenoxy)picolinamide and4-(6-amino-2,3-difluorophenoxy)picolinamide (300 mg, 1.13 mmol) wasconverted to a mixture of4-(2,3-difluoro-4-pivalamidophenoxy)picolinamide and4-(2,3-difluoro-6-pivalamidophenoxy)picolinamide (406 mg). MS (ESI⁺):m/z 350.20 (M+H)⁺.

Prepared in a manner similar to that which is described in Step A ofExample 91. A mixture of4-(2,3-difluoro-4-pivalamidophenoxy)picolinamide and4-(2,3-difluoro-6-pivalamidophenoxy)picolinamide (400 mg) was reactedwith bis(trifluoroacetoxy)iodobenzene to giveN-(4-(2-aminopyridin-4-yloxy)-2,3-difluorophenyl)pivalamide,trifluoroacetic acid salt (120 mg, 24% yield) after prep. HPLCpurification. MS (ESI⁺): m/z 322.23 (M+H)⁺.

C) 4-(4-Amino-2,3-difluorophenoxy)pyridin-2-amine

Prepared in a manner similar to that which is described in Step C ofExample 96. N-(4-(2-Aminopyridin-4-yloxy)-2,3-difluorophenyl)pivalamide,trifluoroacetic acid salt (120 mg, 0.27 mmol) was converted to4-(4-amino-2,3-difluorophenoxy)pyridin-2-amine (52 mg, 81% yield). MS(ESI⁺): m/z 238.11 (M+H)⁺.

D)1-(4-(2-Aminopyridin-4-yloxy)-2,3-difluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,trifluoroacetic acid salt

Prepared in a manner similar to that which is described in Step F ofExample 87. 4-(4-Amino-2,3-difluorophenoxy)pyridin-2-amine (24 mg, 0.10mmol) in THF (3.0 mL) was converted to1-(4-(2-aminopyridin-4-yloxy)-2,3-difluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,trifluoroacetic acid (21 mg, 40% yield). ¹H NMR (DMSO-d₆) δ 11.27 (s,1H), 10.84 (s, 1H), 8.02 (m, 1H), 7.96 (d, 1H, J=8.5 Hz), 7.73 (s, 2H),7.34 (m, 3H), 7.17 (m, 2H), 6.70 (m, 1H), 6.20 (d, 1H, J=2.0 Hz), 3.75(s, 2H); MS (ESI⁺): m/z 417.10 (M+H)⁺.

Example 98

N-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-1-benzyl-5-methyl-1H-pyrazole-3-carboxamide,hydrochloride salt

A) 1-Benzyl-5-methyl-1H-pyrazole-3-carboxylic acid

To a solution of 1-benzylhydrazine dihydrochloride (Aldrich, 0.98 g, 5.0mmol) in EtOH (30 mL) were added DIEA (2.0 mL) and ethyl2,4-dioxopentanoate (0.70 mL, 5.0 mmol). The mixture was stirred at roomtemperature for 12 h and was concentrated in vacuo. The residue wasdissolved in 1 N NaOH (10 mL). The solution was heated at 60° C. for 1h. After cooling down, the solution was extracted with DCM (3×50 mL).The aqueous layer was neutralized to pH 2.0 and then was extracted withEtOAc. The organic layer was washed with brine and dried over MgSO₄. Itwas filtered and concentrated to give1-benzyl-5-methyl-1H-pyrazole-3-carboxylic acid (1.0 g, 92% yield). MS(ESI⁺): m/z 217.12 (M+H)⁺.

B)N-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-1-benzyl-5-methyl-1H-pyrazole-3-carboxamide,hydrochloride salt

4-(4-Amino-2-fluorophenoxy)pyridin-2-amine (Compound B of Example 24, 25mg, 0.11 mmol) was coupled with1-benzyl-5-methyl-1H-pyrazole-3-carboxylic acid (25 mg, 0.11 mmol) in amanner similar to that which is described in Step C of Example 1 to giveN-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)-1-benzyl-5-methyl-1H-pyrazole-3-carboxamidehydrochloride (10 mg, 20% yield) after prep HPLC purification. ¹H NMR(DMSO-d₆) δ 10.64 (s, 1H), 7.8-7.98 (m, 3H), 7.00-7.65 (m, 9H), 6.71 (m,1H), 6.15 (s, 1H), 5.65 (s, 2H), 2.24 (s, 3H); MS (ESI⁺): m/z 418.21(M+H)⁺.

Example 99

2-(4-Fluorobenzylsulfinyl)-N-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)acetamide,hydrochloride salt

A) Ethyl 2-(4-fluorobenzylthio)acetate

To a solution of ethyl 2-mercaptoacetate (Aldrich, 1.0 mL, 9.1 mmol) inacetonitrile (10.0 mL) were added K₂CO₃ (2.76 g, 20.0 mmol) and1-(bromomethyl)-4-fluorobenzene (2.27 g, 12.0 mmol). The mixture wasstirred at room temperature for 12 h. After filtration andconcentration, the residue was purified by flash column chromatographyon SiO₂ to give ethyl 2-(4-fluorobenzylthio)acetate (1.89 g, 91% yield).MS (ESI⁺): m/z 251.08 (M+H)⁺.

B) Ethyl 2-(4-fluorobenzylsulfinyl)acetate

To a solution of ethyl 2-(4-fluorobenzylthio)acetate (1.89 g, 8.29 mmol)in DCM (20.0 mL) at −40° C. was added a solution of m-CPBA (77%, 1.86 g,8.29 mmol) in DCM (20.0 mL) dropwise. The solution was stirred from −40°C. to room temperature overnight. The solution was then quenched withpolymer bound diethylene triamine. After filtration and concentration,the residue was purified by flash chromatography on SiO₂ to give ethyl2-(4-fluorobenzylsulfinyl)acetate (2.0 g, 98% yield). MS (ESI⁺): m/z267.09 (M+H)⁺.

C) 2-(4-Fluorobenzylsulfinyl)acetic acid

To a solution of ethyl 2-(4-fluorobenzylsulfinyl)acetate (1.60 g, 6.55mmol) in THF (10.0 mL) and MeOH (20.0 mL) was added 1 N NaOH (20.0mmol). The mixture was stirred at room temperature for 2 h. Afterremoval of organic solvent under reduced pressure, the remaining aqueoussolution was neutralized with 1 N HCl (25.0 mL). It was extracted withEtOAc (3×100 mL) and the combined organic layer was dried over MgSO₄.The solution was then filtered and concentrated in vacuo to give2-(4-fluorobenzylsulfinyl)acetic acid (1.25 g, 88% yield). MS (ESI⁺):m/z 217.05 (M+H)⁺.

D)2-(4-Fluorobenzylsulfinyl)-N-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)acetamide,hydrochloride salt

4-(4-Amino-2-fluorophenoxy)pyridin-2-amine dihydrochloride (Compound Bof Example 24, 29 mg, 0.10 mmol) was coupled with2-(4-fluorobenzylsulfinyl)acetic acid (22 mg, 0.1 mmol) in a mannersimilar to that which is described in Step C of Example 1 to give2-(4-fluorobenzylsulfinyl)-N-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)acetamide,hydrochloride salt (17 mg, 37% yield). ¹H NMR (DMSO-d₆) δ 10.94 (s, 1H),7.97 (d, 1H, J=7.5 Hz), 7.85 (m, 3H), 7.39-7.45 (m, 4H), 7.23 (t, 2H,J=7.5 Hz), 6.70 (m, 1H), 6.13 (d, 1H, J=2.5 Hz), 4.32 (d, 1H, J=11.0Hz), 4.11 (d, 1H, J=11.0 Hz), 3.98 (d, 1H, J=13.0 Hz), 3.65 (d, 1H,J=13.0 Hz); MS (ESI⁺): m/z 418.26 (M+H)⁺.

Example 100

2-(4-Fluorobenzylsulfonyl)-N-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)acetamide,hydrochloride salt

A) Ethyl 2-(4-fluorobenzylsulfonyl)acetate

To a solution of ethyl 2-(4-fluorobenzylsulfinyl)acetate (370 mg, 1.52mmol) in DCM (5.0 mL) was added m-CPBA (77%, 450 mg, 2.0 mmol). Themixture was stirred at room temperature for 2 h and was then quenchedwith polymer bound diethylene triamine (1.5 g). The reaction mixture wasfiltered and concentrated in vacuo to give ethyl2-(4-fluorobenzylsulfonyl)acetate (360 mg, 91% yield). MS (ESI⁺): m/z283.10 (M+H)⁺.

B) 2-(4-Fluorobenzylsulfonyl)acetic acid

Prepared in a manner similar to that which is described in Step C ofExample 99. Ethyl 2-(4-fluorobenzylsulfonyl)acetate (340 mg, 1.31 mmol)was converted to 2-(4-fluorobenzylsulfonyl)acetic acid (270 mg, 81%yield). MS (ESI⁺): m/z 255.05 (M+H)⁺.

C)2-(4-Fluorobenzylsulfonyl)-N-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)acetamide,hydrochloride salt

4-(4-Amino-2-fluorophenoxy)pyridin-2-amine dihydrochloride (50 mg, 0.17mmol) was coupled with 2-(4-fluorobenzylsulfonyl)acetic acid (33 mg,0.14 mmol) in a manner similar to that which is described in Step C ofExample 1 to give2-(4-fluorobenzylsulfonyl)-N-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)acetamide,hydrochloride salt (30 mg, 45% yield). ¹H NMR (DMSO-d₆) δ 13.40 (s, 1H),11.15 (s, 1H), 7.97 (d, 1H, J=7.0 Hz), 7.80-7.90 (m, 3H), 7.47 (m, 4H),7.26 (t, 2H, J=8.5 Hz), 6.72 (d, 1H, J=7.0 Hz), 6.14 (d, 1H, J=2.0 Hz),4.69 (s, 2H), 4.27 (s, 2H); MS (ESI⁺): m/z 434.15 (M+H)⁺.

Example 101

N-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide,hydrochloride salt

A) Methyl 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate

To a solution of methyl 2-oxo-2H-pyran-3-carboxylate (Aldrich, 2.31 g,15 mmol) in THF (40 mL) and DMF (10 mL) at rt was added 4-fluoroaniline(1.67 g, 15 mmol), and the reaction mixture was stirred for 2.5 h. Solidprecipitation was observed. To the 4-fluoroaniline adduct intermediateformed via Michael addition obtained in situ was added EDCI.HCl (3.85 g,20 mmol) and DMAP (120 mg) at rt. The reaction mixture was stirred at rtovernight. To the reaction mixture were added 1N aq HCl (50 mL) andEtOAc (150 mL), the EtOAc layer was separated, and the aqueous layer waswashed with EtOAc (150 mL), the combined EtOAc layer was dried overMgSO₄ and concentrated in vacuo to obtain a semi-solid material (˜4.4g). To this crude product were added ether (100 mL) and methanol (15mL), stirred, and the solid was filtered to obtain the undesired solidproduct (870 mg). The filtrate solution was concentrated to obtain asemi-solid crude desired product (2.95 g, crude 80%) which was pureenough to use in the next step without further purification. ¹H NMR(DMSO-d₆) δ 8.23 (dd, 1H, J=7.2, 2.2 Hz), 7.57 (dd, 1H, J=6.6, 1.7 Hz),7.32-7.34 (m, 2H), 7.17 (t, 2H, J=8.8 Hz), 6.32 (t, 1H, J=7.1 Hz), 3.89(s, 3H); MS (ESI⁺) m/z 248.2 (M+H)⁺.

B) 1-(4-Fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid

A mixture of methyl1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (crude 2.45g, 12 mmol) and 6 N aq NaOH (2.5 mL) in methanol (60 mL) was stirred atrt for 4 h. To the reaction mixture was added conc HCl (1 mL) slowlywith stirring at rt, and the precipitated solid was filtered, washedwith a small amount water and dried to obtain the desired acid product(2.1 g) as a yellow solid. The filtrate solution was concentrated invacuo. The residue was mixed with water (50 mL) and washed with EtOAc(2×130 mL). The EtOAc layers were dried over MgSO₄ and concentrated invacuo. The residue was triturated with a small amount of ether to obtainthe 2^(nd) crop of product (195 mg, total 2.30 g, 82%). ¹H NMR (DMSO-d₆)δ 8.47 (dd, 1H, J=7.2, 2.2 Hz), 8.19 (dd, 1H, J=6.6, 1.7 Hz), 7.62-7.60(m, 2H), 7.42 (t, 2H, J=8.8 Hz), 6.78 (t, 1H, J=7.1 Hz); MS (ESI⁺) m/z234.2 (M+H)⁺.

C)N-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide,hydrochloride salt

4-(4-Amino-2-fluorophenoxy)pyridin-2-amine (Compound B of Example 24, 58mg, 0.20 mmol) was coupled with1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (47 mg,0.20 mmol) in a manner similar to that which is described in Step C ofExample 1 to giveN-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide,hydrochloride salt (22 mg, 23% yield). ¹H NMR (DMSO-d₆) δ 13.40 (s, 1H),12.13 (s, 1H), 8.58 (d, 1H, J=5.0 Hz), 8.13 (d, 1H, J=5.0 Hz), 8.07 (d,1H, J=10.0 Hz), 7.98 (d, 1H, J=7.5 Hz), 7.89 (s, 2H), 7.40-7.60 (m, 6H),6.72 (m, 2H), 6.17 (d, 1H, J=2.5 Hz); MS (ESI⁺) m/z 435.18 (M+H)⁺.

Example 102

(S)—N¹-(2-Amino-2-oxo-1-phenylethyl)-N³-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)malonamide,hydrochloride salt

A) Ethyl3-(4-(2-carbamoylpyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanoate

To a solution of 4-(4-amino-2-fluorophenoxy)picolinamide (Compound B′ ofExample 24, 1.0 g, 4.0 mmol) in DMF (10.0 mL) were added DIEA (2.0 mL)and ethyl 3-chloro-3-oxopropanoate (Aldrich, 0.75 mL, 6.0 mmol). Themixture was stirred at room temperature for 12 h and more ethyl3-chloro-3-oxopropanoate (0.20 mL, 1.6 mmol) was added. The mixture wasstirred for 2 h and was then diluted with EtOAc (200 mL). It was washedwith H₂O and brine and then dried over MgSO₄. After filtration andconcentration, the residue was triturated with DCM and filtered to giveethyl3-(4-(2-carbamoylpyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanoate(900 mg, 62% yield). MS (ESI⁺) m/z 362.28 (M+H)⁺.

B) Ethyl3-(4-(2-aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanoate

Prepared in a manner similar to that which is described in Step A ofExample 91. Ethyl3-(4-(2-carbamoylpyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanoate(900 mg, 2.5 mmol) in DMF (10.0 mL) was converted to ethyl3-(4-(2-aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanoate (710mg, 86% yield). MS (ESI⁺) m/z 334.26 (M+H)⁺.

C) 3-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanoicacid

Prepared in a manner similar to that which is described in Step C ofExample 99. Ethyl3-(4-(2-aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanoate (700mg, 2.10 mmol) was converted to3-(4-(2-aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanoic acid(630 mg, 98% yield). MS (ESI⁺) m/z 306.20 (M+H)⁺.

D)(S)—N¹-(2-Amino-2-oxo-1-phenylethyl)-N³-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)malonamide,hydrochloride salt

3-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanoic acid(30 mg, 0.10 mmol) was coupled with (S)-2-amino-2-phenylacetamidehydrochloride (Acros, 28 mg, 0.15 mmol) in a manner similar to thatwhich is described in Step C of Example 1 to give(S)—N¹-(2-amino-2-oxo-1-phenylethyl)-N³-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)malonamide,hydrochloride salt (25 mg, 53% yield). ¹H NMR (DMSO-d₆) δ 10.68 (s, 1H),8.80 (d, 1H, J=8.0 Hz), 7.96 (d, 1H, J=7.5 Hz), 7.77-7.90 (m, 4H),7.20-7.45 (m, 8H), 6.70 (m, 1H), 6.12 (s, 1H), 5.39 (d, 1H, J=7.5 Hz),3.48 (d, 1H, J=15.0 Hz), 3.41 (d, 1H, J=15.0 Hz); MS (ESI⁺) m/z 438.26(M+H)⁺.

Example 103

(R)—N¹-(2-Amino-2-oxo-1-phenylethyl)-N³-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)malonamide,hydrochloride salt

3-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanoic acid(Compound C of Example 102, 30 mg, 0.10 mmol) was coupled with(R)-2-amino-2-phenylacetamide hydrochloride (Bachem, 28 mg, 0.15 mmol)in a manner similar to that which is described in Step C of Example 1 togive(R)—N¹-(2-amino-2-oxo-1-phenylethyl)-N³-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)malonamide,hydrochloride salt (14 mg, 30% yield). ¹H NMR (DMSO-d₆) δ 10.65 (s, 1H),8.76 (d, 1H, J=8.0 Hz), 7.92 (d, 1H, J=7.0 Hz), 7.75-7.88 (m, 4H),7.20-7.43 (m, 8H), 6.66 (m, 1H), 6.09 (s, 1H), 5.35 (d, 1H, J=8.0 Hz),3.45 (d, 1H, J=15.0 Hz), 3.37 (d, 1H, J=15.0 Hz); MS (ESI⁺) m/z 438.23(M+H)⁺.

Example 104

(S)-Methyl2-(3-(4-(2-aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanamido)-2-phenylacetate,hydrochloride salt

3-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanoic acid(Compound C of Example 102, 30 mg, 0.10 mmol) was coupled with(s)-methyl 2-amino-2-phenylacetate hydrochloride (Aldrich, 30 mg, 0.10mmol) in a manner similar to that which is described in Step C ofExample 1 to give (S)-methyl2-(3-(4-(2-aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanamido)-2-phenylacetate,hydrochloride salt (21 mg, 43% yield). ¹H NMR (DMSO-d₆) δ 10.58 (s, 1H),9.04 (d, 1H, J=7.0 Hz), 7.97 (d, 1H, J=7.0 Hz), 7.75-7.88 (m, 3H), 7.42(m, 7H), 6.72 (d, 1H, J=7.0 Hz), 6.12 (s, 1H), 5.45 (d, 1H, J=7.0 Hz),3.63 (s, 3H), 3.43-3.38 (m, 2H); MS (ESI⁺) m/z 453.26 (M+H)⁺.

Example 105

(R)-Methyl2-(3-(4-(2-aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanamido)-2-phenylacetate,hydrochloride salt

3-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanoic acid(Compound C of Example 102, 30 mg, 0.10 mmol) was coupled with(R)-methyl 2-amino-2-phenylacetate, hydrochloride salt (Aldrich, 30 mg,0.10 mmol) in a manner similar to that which is described in Step C ofExample 1 to give (R)-methyl2-(3-(4-(2-aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanamido)-2-phenylacetate,hydrochloride salt (25 mg, 51% yield). ¹H NMR (DMSO-d₆) δ 10.58 (s, 1H),9.03 (d, 1H, J=7.0 Hz), 7.96 (d, 1H, J=7.0 Hz), 7.77-7.88 (m, 3H), 7.42(m, 7H), 6.71 (d, 1H, J=7.5 Hz), 6.12 (s, 1H), 5.44 (d, 1H, J=7.0 Hz),3.63 (s, 3H), 3.44-3.38 (m, 2H); MS (ESI⁺) m/z 453.29 (M+H)⁺.

Example 106

N¹-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-N³-cyclopentylmalonamide,hydrochloride salt

3-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanoic acid(Compound C of Example 102, 30 mg, 0.10 mmol) was coupled withcyclopentanamine (Aldrich, 17 mg, 0.2 mmol) in a manner similar to thatwhich is described in Step C of Example 1 to giveN¹-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)-N³-cyclopentylmalonamide,hydrochloride salt (18 mg, 44% yield). ¹H NMR (DMSO-d₆) δ 13.34 (s, 1H),10.66 (s, 1H), 8.15 (d, 1H, J=7.0 Hz), 7.96 (d, 1H, J=7.0 Hz), 7.77-7.88(m, 3H), 7.42 (m, 2H), 6.70 (d, 1H, J=7.5 Hz), 6.12 (s, 1H), 3.98 (m,1H), 3.69 (s, 2H), 1.78 (m, 2H), 1.63 (m, 2H), 1.49 (m, 2H), 1.37 (m,2H); MS (ESI⁺) m/z 373.30 (M+H)⁺.

Example 107

N¹-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-N³-cyclohexylmalonamide,hydrochloride salt

3-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanoic acid(Compound C of Example 102, 30 mg, 0.10 mmol) was coupled withcyclohexanamine (Aldrich, 20 mg, 0.2 mmol) in a manner similar to thatwhich is described in Step C of Example 1 to giveN¹-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)-N³-cyclohexylmalonamide,hydrochloride salt (22 mg, 52% yield). ¹H NMR (DMSO-d₆) δ 14.00 (s, 1H),10.72 (s, 1H), 8.10 (d, 1H, J=7.0 Hz), 7.97 (d, 1H, J=7.0 Hz), 7.88 (m,3H), 7.44 (m, 2H), 6.70 (m, 1H), 6.14 (d, 1H, J=2.0 Hz), 3.54 (m, 1H),3.27 (s, 2H), 1.66-1.75 (m, 4H), 1.52 (m, 1H), 1.15-1.25 (m, 5H); MS(ESI⁺) m/z 387.32 (M+H)⁺.

Example 108

N¹-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-N³-neopentylmalonamide,hydrochloride salt

3-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanoic acid(Compound C of Example 102, 30 mg, 0.10 mmol) was coupled with2,2-dimethylpropan-1-amine (Aldrich, 12 mg, 0.2 mmol) in a mannersimilar to that which is described in Step C of Example 1 to giveN¹-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)-N³-neopentylmalonamide,hydrochloride salt (13 mg, 32% yield). ¹H NMR (DMSO-d₆) δ 13.34 (s, 1H),10.69 (s, 1H), 8.08 (m, 1H), 7.96 (d, 1H, J=7.0 Hz), 7.87 (m, 3H), 7.44(m, 2H), 6.70 (m, 1H), 6.13 (d, 1H, J=2.0 Hz), 3.34 (s, 2H), 2.91 (d,2H, J=6.5 Hz), 0.84 (s, 9H); MS (ESI⁺) m/z 375.32 (M+H)⁺.

Example 109

(S)-2-(3-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanamido)-2-phenylaceticacid, hydrochloride salt

Following a procedure similar to that which is described in Step C ofExample 99, (S)-methyl2-(3-(4-(2-aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanamido)-2-phenylacetatehydrochloride (Compound D of Example 102, 14 mg, 0.028 mmol) washydrolyzed to give(s)-2-(3-(4-(2-aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanamido)-2-phenylaceticacid, hydrochloride salt (13 mg, 97% yield). ¹H NMR (DMSO-d₆) δ 13.20(s, 1H), 10.57 (s, 1H), 8.92 (d, 1H, J=7.0 Hz), 7.95 (d, 1H, J=7.0 Hz),7.87 (d, 1H, J=11.0 Hz), 7.70 (s, 2H), 7.41 (m, 8H), 6.69 (d, 1H, J=7.5Hz), 6.12 (d, 1H, J=2.0 Hz), 5.35 (d, 1H, J=7.5 Hz), 3.42 (s, 2H); MS(ESI⁺) m/z 439.27 (M+H)⁺.

Example 110

N-(4-(2-(3-(Dimethylamino)propylamino)pyridin-4-yloxy)-3-fluorophenyl)-2,6-difluorobenzamide,hydrochloride salt

A) N-(4-(2-Chloropyridin-4-yloxy)-3-fluorophenyl)-2,6-difluorobenzamide

A solution 4-(2-chloropyridin-4-yloxy)-3-fluorobenzenamine (Compound Bof Example 20, 64 mg, 0.27 mmol), THF (1 ml), Et₃N (100 μL) was treateddropwise with 2,6-difluorobenzoyl chloride (Aldrich, 33 μL, 0.27 mmol)and the mixture was stirred at rt for 30 min. The mixture waspartitioned between EtOAc and saturated aq. NaHCO₃ and the EtOAc phasewas separated, dried (MgSO₄) and concentrated in vacuo to give the titlecompound (102 mg, 100%) as white solid. MS (ESI⁺): m/z 418.18 (M+H)⁺.

B)N-(4-(2-(3-(Dimethylamino)propylamino)pyridin-4-yloxy)-3-fluorophenyl)-2,6-difluorobenzamide,hydrochloride salt

A mixture ofN-(4-(2-chloropyridin-4-yloxy)-3-fluorophenyl)-2,6-difluorobenzamide (70mg, 0.19 mmol), 3-(dimethylamino)propylamine (44 mL, 0.35 mmol), Cs₂CO₃(85 mg, 0.26 mmol) and CuCl (17 mg, 0.17 mmol) in a screw capped vialwas purged with N₂. NMP and 2,2,6,6,-tetramethyl-3,5-heptanedione (31mg, 0.17 mmol) were added to the mixture which was then heated at 120°C. for 4 h. The mixture was cooled, partitioned between EtOAc andsaturated aq. NaHCO₃ solution and the EtOAc phase was separated, dried(MgSO₄) and concentrated in vacuo to give the crude product.Purification of the residue by preparative HPLC (Column C) andconversion to the hydrochloride salt was carried out in a similar manneras Step D of Example 33 to give the title compound (7 mg, 7%) as anoff-white solid. MS (ESI⁺): m/z 517.37 (M+H)⁺.

Example 111

N-(4-(2-Amino-3-(4-(2-amino-2-oxoethyl)phenyl)pyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide,hydrochloride salt

A solution of2-(4-(2-amino-4-(4-amino-2-fluorophenoxy)pyridin-3-yl)phenyl)acetamide(Compound C of Example 78, 18 mg, 0.05 mmol) in DMF (1.5 mL) was treatedwith 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid(Compound B of Example 101, 11 mg, 0.05 mmol), DIPEA (10 μL, 0.06 mmol)and TBTU (19 mg, 0.06 mmol). The mixture was stirred at room temperaturefor 40 h. The mixture was concentrated under vacuum and the residue waspurified by preparative HPLC (Column A) to give the title compound as aTFA salt. The TFA salt was dissolved in anhydrous MeOH and treated with1 M HCl/Et₂O at 0° C. and stirred for 5 min. The mixture was thenconcentrated in vacuo to give the title compound (15 mg, 47%) as ayellow solid. ¹H NMR (DMSO-d₆) δ 12.11 (s, 1H), 8.56 (dd, 1H, J=2.2, 7.1Hz), 8.13 (dd, 1H, J=2.2, 6.7 Hz), 8.00 (dd, 1H, J=2.2, 12.6 Hz), 7.96(d, 1H, J=7.7 Hz), 7.60-7.57 (m, 2H), 7.48-7.33 (m, 10H), 6.94 (s, 1H),6.72 (dd, 1H, J=7.2, 7.2 Hz), 6.38 (d, 1H, J=7.2 Hz), 3.95 (s, 2H); MS(ESI⁺): m/z 568.23 (M+H)⁺.

Example 112

1-(4-(2-Aminopyridin-4-yloxy)-2,5-difluorophenyl)-3-(2-(4-fluorophenyl)-acetyl)urea,hydrochloric acid salt

A) 1-((2,5-Difluoro-4-nitrophenoxy)methyl)benzene

A mixture of 2,4,5-trifluoronitrobenzene (5.4 g, 30.8 mmol),benzylalcohol (3.2 mL, 30.8 mmol) and potassium carbonate (6.4 g, 46.1mmol), in DMF (20 mL), was stirred at ambient temperature for 72 h.Water (60 mL) was added and the mixture was cooled at 4° C. for 24 h.The resultant precipitate was filtered, rinsed with water and dried invacuo to afford the product (7.5 g, 92%) as a pale yellow solid. ¹H NMR(CDCl₃) δ 7.90-7.94 (m, 1H), 7.38-7.44 (m, 5H), 6.85-6.90 (m, 1H), 5.22(s, 2H).

B) 4-Amino-2,5-difluorophenol

To a flask charged with 1-((2,5-difluoro-4-nitrophenoxy)methyl)benzene(4.1 g, 15.6 mmol), which was sequentially evacuated and then purgedwith nitrogen three times, was added 10% palladium on carbon (0.40 g).To the solids, under a nitrogen atmosphere, was added anhydrous methanol(100 mL). The mixture was then stirred under a hydrogen atmosphere for16 h. Nitrogen was bubbled through the reaction mixture for thirtyminutes, before the mixture was filtered through a pad of Celite®, whichwas then rinsed with methanol. The filtrate was concentrated in vacuo,then azeotroped with toluene to afford the title compound as a darkbrown solid (2.2 g, 99%). ¹H NMR (DMSO-d₆) δ 9.05 (br s, 1H), 6.53-6.65(m, 2H), 4.68 (s, 2H); MS (ESI⁺) m/z 146 (M+H)⁺.

C) 4-(4-Amino-2,5-difluorophenoxy)picolinamide

To a mixture of potassium hydride (30-35% dispersion in mineral oil, 1.9g, 13.9 mmol) in DMF (30 mL) was added 4-amino-2,5-difluorophenol (1.7g, 11.6 mmol) as a solution in DMF (5 mL). After one hour of stirring atambient temperature, 4-chloropicolinamide (1.8 g, 11.6 mmol) was addedand the reaction mixture was heated to 100° C. for 135 h. The mixturewas cooled to room temperature, quenched with 10% aqueous lithiumchloride and then extracted three times with EtOAc. The combined organiclayers were dried (MgSO₄), filtered and concentrated in vacuo. Theresultant solid was partitioned between chloroform and water. Theorganic layer was washed with brine, dried (MgSO₄), filtered andconcentrated in vacuo to a solid (3.0 g, 98%). ¹H NMR (DMSO-d₆) δ8.51-8.57 (m, 1H), 8.14 (br s, 1H), 7.74 (br s, 1H), 7.37-7.38 (m, 1H),7.17-7.30 (m, 2H), 6.74-6.80 (m, 1H), 5.62 (s, 2H); MS (ESI⁺) m/z 266(M+H)⁺.

D)1-(4-(2-Carbamoylpyridin-4-yloxy)-2,5-difluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea

To a homogeneous mixture of 4-(4-amino-2,5-difluorophenoxy)picolinamide(0.15 g, 0.57 mmol) in THF (5 mL) was added diisopropylethylamine (0.10mL, 0.57 mmol). The mixture was stirred for two minutes at ambienttemperature before 2-(4-fluorophenyl)acetyl isocyanate (Compound D ofExample 11, 0.36 M in toluene, 2.0 mL, 0.72 mmol) was added. After 3.5hours, 2-(4-fluorophenyl)acetyl isocyanate (0.36 M in toluene, 2.0 mL,0.72 mmol) was added to the reaction mixture. After an additional twohours, 2-(4-fluorophenyl)acetyl isocyanate (0.36 M in toluene, 2.0 mL,0.72 mmol) was added to the reaction mixture. The mixture was thenstirred for 16 hours before being concentrated in vacuo. The residue wastreated with Et₂O and sonication and the resultant white solid wasremoved by filtration. The solid was treated with Et₂O and sonicationtwo more times before vacuum filtration afforded a white solid (0.23 g,91%). ¹H NMR (DMSO-d₆) δ 11.29 (s, 1H), 10.92 (s, 1H), 8.56 (d, 1H,J=5.6 Hz), 8.21-8.26 (m, 1H), 8.16 (br s, 1H), 7.76 (br s, 1H),7.66-7.71 (m, 1H), 7.12-7.44 (m, 6H), 3.77 (s, 2H); MS (ESI⁺) m/z 445(M+H)⁺.

E)1-(4-(2-Aminopyridin-4-yloxy)-2,5-difluorophenyl)-3-(2-(4-fluorophenyl)-acetyl)urea,hydrochloric acid salt

Bis(trifluoroacetoxy)iodobenzene (Aldrich, 0.18 g, 0.42 mmol) was addedto a solution of1-(4-(2-carbamoylpyridin-4-yloxy)-2,5-difluorophenyl)-3-(2-(4-fluorophenyl)-acetyl)urea(0.13 g, 0.30 mmol), water (0.01 mL, 0.60 mmol) and pyridine (0.05 mL,0.66 mmol) in DMF (2 mL) at room temperature. After ten minutes,additional DMF (2 mL) was added. The reaction mixture was then stirredfor 16 hours before being concentrated in vacuo to approximately onehalf of its original volume. The resultant mixture was partitionedbetween 6 N HCl and Et₂O, the aqueous solution extracted with Et₂O andthe combined organic layers discarded. The aqueous layer was neutralizedwith NaHCO₃(aq) and extracted with EtOAc. The combined organic layerswere dried (Na₂SO₄), filtered and concentrated in vacuo. The residue waspurified by silica gel chromatography (eluting with 0-5% MeOH in CHCl₃)and the appropriate fractions were concentrated in vacuo. The residuewas dissolved in THF (1 mL), cooled to 0° C. and treated with HCl (4 Nin dioxane, 0.5 mL, 2.0 mmol). The reaction mixture was allowed to warmto room temperature and stirred for one hour, before being lyophilizedto afford the title compound (73 mg, 53%) as a white solid. ¹H NMR(DMSO-d₆) δ 13.54 (br s, 1H), 11.35 (s, 1H), 10.95 (s, 1H), 8.24-8.28(m, 1H), 7.95-8.01 (m, 3H), 7.73-7.77 (m, 1H), 7.35-7.39 (m, 2H),7.16-7.20 (m, 2H), 6.72-6.74 (m, 1H), 6.25 (s, 1H), 3.78 (s, 2H); HRMS(ESI⁺): 417.1175 (M+H)⁺ calcd., 417.1187 (M+H)⁺ found.

Example 113

1-(4-(2-Aminopyridin-4-yloxy)-3,5-difluorophenyl)-3-(2-(4-fluorophenyl)-acetyl)urea,trifluoroacetic acid salt

A) 2,6-Difluoro-4-nitrophenol

2,6-Difluorophenol (10.0 g, 76.9 mmol) was converted to the titlecompound (12.7 g, 94%) in a manner similar to the conditions describedby Kirk et al. J. Heterocyclic Chem. 1976, 13, 1253. ¹H NMR (CDCl₃) δ12.15 (br s, 1H), 8.01-8.10 (m, 2H).

B) 4-Amino-2,6-difluorophenol

2,6-Difluoro-4-nitrophenol (2.1 g, 12.1 mmol) was converted to the titlecompound (1.7 g, 99%) in a manner similar to that described byDemopoulos et al. J. Med. Chem. 2004, 47, 2706. MS (ESI⁺) m/z 146(M+H)⁺.

C) 4-(4-Amino-2,6-difluorophenoxy)picolinamide

4-Chloropicolinamide (0.47 g, 3.0 mmol) was converted to the titlecompound (0.23 g, 29%) in a manner similar to the preparation ofCompound C of Example 112, except that 4-amino-2,6-difluorophenol (0.44g, 3.0 mmol) was used instead of 4-amino-2,5-difluorophenol. ¹H NMR(DMSO-d₆) δ 8.60 (d, 1H, J=5.6 Hz), 8.22 (br s, 1H), 7.83 (br s, 1H),7.45-7.46 (m, 1H), 7.30-7.32 (m, 1H), 6.43-6.49 (m, 2H), 5.94 (s, 2H);MS (ESI⁺) m/z 266 (M+H)⁺.

D)1-(4-(2-Carbamoylpyridin-4-yloxy)-3,5-difluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea

4-(4-Amino-2,6-difluorophenoxy)picolinamide (104 mg, 0.39 mmol) wasconverted to the title compound (91 mg, 52%) in a manner similar to thepreparation of Compound D of Example 112. ¹H NMR (DMSO-d₆) δ 11.07 (s,1H), 10.62 (s, 1H), 8.50 (d, 1H, J=5.6 Hz), 8.11 (br s, 1H), 7.72 (br s,1H), 7.61 (m, 2H), 7.36-7.37 (d, 1H, J=2.3 Hz), 7.23-7.31 (m, 3H), 7.11(m, 2H), 3.69 (s, 2H); HRMS (ESI⁺), 445.1124 (M+H)⁺ calcd., 445.1117(M+H)⁺ found.

E)1-(4-(2-Aminopyridin-4-yloxy)-3,5-difluorophenyl)-3-(2-(4-fluorophenyl)-acetyl)urea,trifluoroacetic acid salt

1-(4-(2-Carbamoylpyridin-4-yloxy)-3,5-difluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea(87 mg, 0.20 mmol) was converted to the title compound in a mannersimilar to the preparation of Compound E of Example 112, except that thecrude product was purified by preparative HPLC (YMC S10 ODS, 30×500 mm,30 minute gradient from 58% to 90% aqueous methanol with 0.1% TFA). Theappropriate fractions were combined and lyophilized to afford the titlecompound (23 mg, 22%) as a white solid. ¹H NMR (DMSO-d₆) δ 11.09 (s,1H), 10.63 (s, 1H), 7.92 (d, 1H, J=7.2 Hz), 7.62-7.72 (m, 4H), 7.27-7.31(m, 2H), 7.09-7.14 (m, 2H), 6.68-6.70 (m, 1H), 6.17-6.18 (m, 1H), 3.69(s, 2H); MS (ESI⁺) m/z 417 (M+H)⁺.

Example 114

N-(4-(2-Aminopyridin-4-yloxy)-2,5-difluorophenyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide,hydrochloric acid salt

A)4-(2,5-Difluoro-4-(2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamido)-phenoxy)picolinamide

To a homogeneous mixture of2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid (Compound C ofExample 57, 43 mg, 0.20 mmol) in DMF (4 mL) was added1-hydroxy-benzotriazole hydrate (22 mg, 0.16 mmol). The mixture wasstirred until homogeneous before1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (102 mg,0.53 mmol) was added. After two minutes,4-(4-amino-2,5-difluorophenoxy)picolinamide (Compound C of Example 112,53 g, 0.20 mmol) was added and the reaction mixture stirred, at ambienttemperature for 17 h. The reaction mixture was then warmed to 40° C. andstirred for an additional 143 h. After cooling to ambient temperature,the mixture was partitioned between EtOAc and 10% LiCl (aq). The organiclayer was washed twice with 10% LiCl (aq), then concentrated in vacuo.The residue was purified by silica gel chromatography (eluting with 1:3hexane/EtOAc) and the appropriate fractions were concentrated in vacuoto afford the title compound (45 mg, 49%). MS (ESI⁺) m/z 463 (M+H)⁺.

B)N-(4-(2-Aminopyridin-4-yloxy)-2,5-difluorophenyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide,hydrochloric acid salt

4-(2,5-Difluoro-4-(2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamido)-phenoxy)picolinamide(45 mg, 0.10 mmol) was converted to the title compound (19 mg, 40%) in amanner similar to the preparation of Compound E of Example 112. ¹H NMR(DMSO-d₆) δ 13.40 (br s, 1H), 12.47 (s, 1H), 8.53-8.57 (m, 2H),8.12-8.13 (m, 1H), 7.92-7.93 (m, 1H), 7.83 (s, 2H), 7.66-7.71 (m, 1H),7.46-7.53 (m, 5H), 6.66-6.72 (m, 2H), 6.19 (s, 1H); HRMS (ESI⁺),435.1269 (M+H)⁺ calcd., 435.1258 (M+H)⁺ found.

Example 115

N-(4-(2-Aminopyridin-4-yloxy)-2,5-difluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide,hydrochloric acid salt

A)4-(2,5-Difluoro-4-(1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)picolinamide

To a homogeneous mixture of1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (CompoundB of Example 101, 50 mg, 0.21 mmol) and4-(4-amino-2,5-difluorophenoxy)picolinamide (Compound C of Example 112,69 mg, 0.26 mmol) in DMF (3 mL) was added DIPEA (0.05 mL, 0.26 mmol) andO-benzotriazol-1-yl-N,N,N′,N′-bis(tetramethylene)-uraniumhexafluorophosphate (TBTU) (83 mg, 0.26 mmol). The resulting solutionwas stirred for 18 hours before being quenched with 10% LiCl (aq). Themixture was partitioned between EtOAc and 10% LiCl (aq), the layersseparated, and the aqueous layer extracted with EtOAc. The combinedorganic layers were washed twice with 10% LiCl (aq), then concentratedin vacuo. The residue was purified by silica gel chromatography (elutingwith 1:3 hexane/EtOAc) and the appropriate fractions were concentratedin vacuo to afford the title compound (22 mg, 22%). MS (ESI⁺) m/z 481(M+H)⁺.

B)N-(4-(2-Aminopyridin-4-yloxy)-2,5-difluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide,hydrochloric acid salt

4-(2,5-Difluoro-4-(1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)picolinamide(22 mg, 0.04 mmol) was converted to the title compound (21 mg, 95%) in amanner similar to the preparation of Compound E of Example 112. ¹H NMR(DMSO-d₆) δ 13.71 (br s, 1H), 12.43 (s, 1H), 8.48-8.57 (m, 2H),8.10-8.13 (m, 1H), 7.93-7.95 (m, 3H), 7.61-7.70 (m, 1H), 7.53-7.56 (m,2H), 7.29-7.39 (m, 2H), 6.64-6.72 (m, 2H), 6.10 (s, 1H); HRMS (ESI⁺),453.1175 (M+H)⁺ calcd., 453.1168 (M+H)⁺ found.

Example 116

(±)-N′-(4-(2-Aminopyridin-4-yloxy)-2,5-difluorophenyl)-N³-(1-phenylethyl)malonamide,hydrochloric acid salt

A) Ethyl3-(4-(2-carbamoylpyridin-4-yloxy)-2,5-difluorophenylamino)-3-oxopropanoate

4-(4-Amino-2,5-difluorophenoxy)picolinamide (Compound C of Example 112,1.0 g, 3.9 mmol) was converted to the title compound (320 mg, 22%) in amanner similar to the preparation of Compound A of Example 102. ¹H NMR(DMSO-d₆) δ 10.32 (s, 1H), 8.54 (d, 1H, J=5.5 Hz), 8.14-8.17 (m, 2H),7.75 (br s, 1H), 7.61-7.65 (m, 1H), 7.42-7.43 (m, 1H), 7.24-7.25 (m,1H), 4.12 (q, 2H, J=7.2 Hz), 3.60 (s, 2H), 1.20 (t, 3H, J=7.2 Hz); MS(ESI⁺) m/z 380 (M+H)⁺.

B)3-(4-(2-Carbamoylpyridin-4-yloxy)-2,5-difluorophenylamino)-3-oxopropanoicacid

To a heterogeneous mixture of ethyl3-(4-(2-carbamoylpyridin-4-yloxy)-2,5-difluorophenylamino)-3-oxopropanoate(305 mg, 0.80 mmol) in MeOH (8 mL) was added aqueous 1 M NaOH (1.70 mL,1.70 mmol). After one hour of stirring, the mixture was acidified withaqueous 1N HCl (5 mL). The reaction was extracted with EtOAc before thecombined organic layers were dried (MgSO₄), filtered and concentrated invacuo to afford the title compound (317 mg) which was used withoutfurther purification. HRMS (ESI⁺), 352.0745 (M+H)⁺ calcd., 352.0752(M+H)⁺ found.

C)(±)-4-(2,5-Difluoro-4-(3-oxo-3-(1-phenylethylamino)propanamido)-phenoxy)picolinamide

To a homogeneous mixture of3-(4-(2-carbamoylpyridin-4-yloxy)-2,5-difluorophenylamino)-3-oxopropanoicacid (89 mg, 0.25 mmol) and (±)-1-phenyl-ethanamine (Aldrich, 0.05 mL,0.38 mmol) in DMF (3 mL) was added DIPEA (0.07 mL, 0.38 mmol) andO-benzotriazol-1-yl-N,N,N′,N′-bis(tetramethylene)uraniumhexafluorophosphate (TBTU) (121 mg, 0.38 mmol). The resulting solutionwas stirred for 15 hours before being quenched with 10% LiCl (aq). Themixture was partitioned between EtOAc and 10% LiCl (aq), the layersseparated, and the aqueous layer extracted with EtOAc. The combinedorganic layers were washed twice with 10% LiCl (aq), then concentratedin vacuo. The residue was purified by silica gel chromatography (elutingwith 1:3 hexane/EtOAc) and the appropriate fractions were concentratedin vacuo to afford the title compound (42 mg, 37%). HRMS (ESI⁺),455.1532 (M+H)⁺ calcd., 455.1528 (M+H)⁺ found.

D)(±)—N¹-(4-(2-Aminopyridin-4-yloxy)-2,5-difluorophenyl)-N³-(1-phenyl-ethyl)malonamide,hydrochloric acid salt

(±)-4-(2,5-Difluoro-4-(3-oxo-3-(1-phenylethylamino)propanamido)phenoxy)-picolinamide(41 mg, 0.09 mmol) was converted to the title compound (26 mg, 62%) in amanner similar to the preparation of Compound E of Example 112. ¹H NMR(DMSO-d₆) δ 10.46 (s, 1H), 8.70 (d, 1H, J=7.8 Hz), 8.21-8.26 (m, 1H),8.00 (d, 1H, J=7.2 Hz), 7.89 (s, 2H), 7.67-7.72 (m, 1H), 7.22-7.36 (m,5H), 6.73-6.76 (m, 1H), 6.21-6.22 (m, 1H), 4.93-4.96 (m, 1H), 3.57 (s,2H), 1.35 (d, 3H, J=7.0 Hz); HRMS (ESI⁺), 427.1582 (M+H)⁺ calcd.,427.1574 (M+H)⁺ found.

Example 117

(±)—N¹-(4-(2-Aminopyridin-4-yloxy)-2,5-difluorophenyl)-N³-(cyano(phenyl)-methyl)malonamide,trifluoroacetic acid salt

A)(±)-4-(4-(3-(Cyano(phenyl)methylamino)-3-oxopropanamido)-2,5-difluorophenoxy)picolinamide

3-(4-(2-Carbamoylpyridin-4-yloxy)-2,5-difluorophenylamino)-3-oxopropanoicacid (Compound B of Example 116, 70 mg, 0.20 mmol) was converted to thetitle compound (67 mg, 72%) in a manner similar to the preparation ofCompound C of Example 116, except that (±)-2-amino-2-phenylacetonitrilehydrochloride (Aldrich, 47 mg, 0.28 mmol) was used instead of(±)-1-phenylethanamine. MS (ESI⁺) m/z 466 (M+H)⁺.

B)(±)—N1-(4-(2-Aminopyridin-4-yloxy)-2,5-difluorophenyl)-N3-(cyano-(phenyl)methyl)malonamide,trifluoroacetic acid salt

(±)-4-(4-(3-(Cyano(phenyl)methylamino)-3-oxopropanamido)-2,5-difluoro-phenoxy)picolinamide(65 g, 0.14 mmol) was converted to the title compound in a mannersimilar to the preparation of Compound E of Example 112, except that thecrude product was purified by preparative HPLC (YMC S10 ODS, 30×500 mm,30 minute gradient from 34% to 90% aqueous methanol with 0.1% TFA). Theappropriate fractions were combined and lyophilized to afford the titlecompound (38 mg, 49%) as a white solid. ¹H NMR (DMSO-d₆) δ 10.40 (s,1H), 9.47 (d, 1H, J=7.63 Hz), 8.21-8.26 (m, 1H), 7.99 (d, 1H, J=7.2 Hz),7.86 (br s, 2H), 7.68-7.73 (m, 1H), 7.43-7.54 (m, 5H), 6.74-6.77 (m,1H), 6.20-6.22 (m, 2H), 3.55 (m, 2H); HRMS (ESI⁺), 438.1378 (M+H)⁺calcd., 438.1374 (M+H)⁺ found.

Example 118

(±)—N¹-(2-Amino-1-phenylethyl)-N³-(4-(2-aminopyridin-4-yloxy)-2,5-difluorophenyl)malonamide,bistrifluoroacetic acid salt

(±)—N¹-(4-(2-Aminopyridin-4-yloxy)-2,5-difluorophenyl)-N³-(cyano(phenyl)-methyl)malonamide,trifluoroacetic acid salt (Compound B of Example 117, 21 mg, 0.04 mmol)was converted to the title compound in a manner similar to theconditions described by Campiani, et al. (Tetrahedron 2002, 58, 3689).The cobalt boride was purchased from Alfa Aesar. The crude product waspurified by preparative HPLC (YMC S5 ODS, 10×250 mm, 30 minute gradientfrom 10% to 90% aqueous methanol with 0.1% TFA). Appropriate fractionswere combined and lyophilized to afford the title compound (5 mg, 21%)as a white solid. ¹H NMR (DMSO-d₆) δ 10.39 (s, 1H), 8.72 (d, 1H, J=8.5Hz), 8.12-8.17 (m, 1H), 7.90-7.94 (m, 3H), 7.59-7.63 (m, 2H), 7.27-7.34(m, 4H), 6.60-6.62 (m, 1H), 6.09-6.10 (m, 1H), 5.09-5.10 (m, 1H),3.10-3-50 (m, 6H); HRMS (ESI⁺), 442.1691 (M+H)⁺ calcd., 442.1678 (M+H)⁺found.

Example 119

N-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxamide

A) 1-(4-Fluorophenyl)-2-oxopyrrolidine-3-carboxylic acid

To a solution of 6,6-dimethyl-5,7-dioxaspiro[2.5]-octane-4,8-dione(Aldrich, 51 mg, 0.3 mmol) in DMF (0.5 mL) at room temperature was added4-fluoroaniline (Aldrich, 33 mg, 0.3 mmol). The reaction mixture washeated at 90° C. for 2 h, cooled to room temperature, and used directlyin the next step.

B)N-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxamide

To a mixture of 1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxylic acid(0.3 mol), 4-(4-amino-2-fluorophenoxy)pyridin-2-amine (Compound B ofExample 24, 21.9 mg, 0.1 mmol) in DMF (0.5 ml), was added HATU (76 mg,0.2 mmol) and followed by diisopropylethylamine (0.1 mL, 0.57 mmol). Thereaction mixture was stirred at room temperature overnight and was thenquenched with 2 mL of methanol. The reaction mixture was purified byprep HPLC. The desired fractions were combined, neutralized with sat.aq. NaHCO₃ solution, and concentrated in vacuo to afford the titlecompound (18 mg, 43%) as a white solid. ¹H NMR (DMSO-d₆) δ 10.76 (br s,1H), 7.95 (d, 1H, J=7.2 Hz), 7.91 (m, 1H), 7.68 (m, 2H), 7.50 (m, 1H),7.44 (t, 1H, J=10.0 Hz), 7.24 (m, 2H), 6.70 (m, 1H), 6.11 (d, 1H, J=2.8Hz), 3.91 (m, 2H), 3.78 (t, 1H, J=5.0 Hz), 2.41 (m, 2H); MS (ESI⁺) m/z425.15 (M+H)⁺.

Example 120

N-(4-(3-Aminopyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

A)N-(3-Fluoro-4-(3-nitropyridin-4-yloxy)phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

Prepared from 3-fluoro-4-(3-nitropyridin-4-yloxy)benzenamine (Compound Aof Example 72) in a manner similar to that of Example 62 to give thetitle compound (89%) as a tan solid. ¹H NMR (CD₃OD) δ 9.13 (s, 1H), 8.72(dd, 1H, J=8, 4 Hz), 8.60 (d, 1H, J=6 Hz), 8.07 (d, 1H, J=12 Hz),8.01-7.99 (m, 1H), 7.58-7.55 (m, 2H), 7.45 (t, 1H, J=8 Hz), 7.40-7.32(m, 3H), 6.99 (d, 1H, J=4 Hz), 6.76 (t, 1H, J=8 Hz); MS (ESI⁺) m/z465.18 (M+H)⁺.

B)N-(4-(3-Aminopyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

Prepared in a similar manner as Step C of Example 59. The crude productwas purified by flash chromatography on silica gel (10% MeOH/EtOAc) togive the HCl salt of the title compound (58%) as an off-white solid. ¹HNMR (DMSO-d₆) δ 12.07 (s, 1H), 8.59 (dd, 1H, J=7.6, 2.4 Hz), 8.14 (dd,1H, J=6.4, 2 Hz), 8.04 (s, 1H), 7.99 (dd, 1H, J=13.2, 2.4 Hz), 7.66 (d,1H, J=5.2 Hz), 7.63-7.60 (m, 2H), 7.46-7.41 (m, 3H), 7.22 (t, 1H, J=9.2Hz), 6.74 (t, 1H, J=7.2 Hz), 6.46 (d, 1H, J=5.2 Hz), 5.26 (br s, 2H); MS(ESI⁺): m/z 435.26 (M+H)⁺.

Example 121

N-(3-Fluoro-4-(3-(pyrrolidin-3-ylmethylamino)pyridin-4-yloxy)phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide,hydrochloride salt

ToN-(4-(3-aminopyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide(Example 120, 30 mg, 0.07 mmol) in DCE (1 mL) was added3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (CB Research andDevelopment Inc., 28 mg, 0.14 mmol), acetic acid (5 uL, 0.084 mmol),then sodium triacetoxyborohydride (23 mg, 0.104 mmol). After stirring atrt for 6 h, a second portion (23 mg) of sodium triacetoxyborohydride wasadded. After stirring at rt for 2 h, the reaction mixture was chargedwith 4N HCl in dioxane (5 mL) and stirred an additional 1 h at rt. Thereaction was diluted with 10% MeOH/EtOAc (10 mL) and washed withsaturated sodium bicarbonate solution (10 mL). The aqueous phase wasback-extracted with 10 mL of 10% MeOH/EtOAc and the combined organiclayers were dried over anhydrous Na₂SO₄ and then concentrated in vacuo.The resulting crude product was purified by prep HPLC. The appropriatefractions were concentrated to remove methanol and then made basic withsaturated aqueous sodium bicarbonate solution. The aqueous solution wasextracted with 10% MeOH/EtOAc (3×20 mL) and the pooled organic extractswere dried over anhydrous Na₂SO₄ and then concentrated in vacuo. Theresidue was lyophilized from acetonitrile (1 mL)/water (3 mL)/1N aq HCl(0.2 mL) to give the HCl salt of the title compound (25 mg, 60%) as awhite solid. ¹H NMR (DMSO-d₆) δ 12.17 (s, 1H), 8.59 (dd, 1H, J=7.6, 2Hz), 8.30 (s, 1H), 8.16 (dd, 1H, J=6.4, 2 Hz), 8.10 (dd, 1H, J=12.8, 2Hz), 8.00 (d, 1H, J=6.4 Hz), 7.64-7.58 (m, 3H), 7.52 (t, 1H, J=9.2 Hz),7.46-7.42 (m, 2H), 7.00 (d, 1H, J=6 Hz), 6.75 (t, 1H, J=7.2 Hz),3.72-3.64 (m, 3H), 3.37-3.26 (m, 1H), 3.17-3.10 (m, 1H), 2.97-2.92 (m,1H), 2.74-2.66 (m, 1H), 2.10-2.03 (m, 1H), 1.75-1.68 (m, 1H); MS (ESI⁺)m/z 518.29 (M+H)⁺.

Example 122

N-(4-(3-(2-Aminoethylamino)pyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide,hydrochloride salt

Prepared in a similar manner as Example 121 to give the HCl salt of thetitle compound (52%) as a white solid. ¹H NMR (DMSO-d₆) δ 12.10 (s, 1H),8.52 (dd, 1H, J=7.6, 2.4 Hz), 8.25 (s, 1H), 8.09 (dd, 1H, J=6.8, 2.4Hz), 8.06-8.02 (m, 1H), 7.96 (d, 1H, J=6.4 Hz), 7.56-7.52 (m, 3H),7.42-7.34 (m, 3H), 6.92 (d, 1H, J=6 Hz), 6.68 (t, 1H, J=6.8 Hz),3.50-3.48 (m, 2H), 3.00-2.99 (m, 2H); MS (ESI⁺) m/z 478.29 (M+H)⁺.

Example 123

N-(3-Fluoro-4-(3-(piperidin-2-ylmethylamino)pyridin-4-yloxy)phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide,hydrochloride salt

Prepared in a similar manner as Example 121 to give the HCl salt of thetitle compound (71%) as a yellow solid. ¹H NMR (DMSO-d₆) δ 12.17 (s,1H), 8.59 (dd, 1H, J=7.2, 2 Hz), 8.51 (s, 1H), 8.16 (dd, 1H, J=6.8, 2Hz), 8.11 (dd, 1H, J=13.2, 2.4 Hz), 8.02 (d, 1H, J=6.4 Hz), 7.63-7.58(m, 3H), 7.51 (t, 1H, J=8.8 Hz), 7.46-7.41 (m, 2H), 7.01 (d, 1H, J=6Hz), 6.75 (t, 1H, J=6.8 Hz), 3.70-3.63 (m, 1H), 3.52-3.45 (m, 1H),3.30-3.27 (m, 2H), 2.86-2.84 (m, 1H), 1.95-1.93 (m, 1H), 1.80-1.62 (m,3H), 1.58-1.44 (m, 2H); MS (ESI⁺) m/z 532.31 (M+H)⁺.

Example 124

N-(4-(3-(3-(Dimethylamino)-2,2-dimethylpropylamino)pyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide,hydrochloride salt

Prepared in a similar manner as Example 121 to give the HCl salt of thetitle compound (58%) as a white solid. ¹H NMR (DMSO-d₆) δ 12.10 (s, 1H),8.57 (s, 1H), 8.52 (dd, 1H, J=7.6, 2 Hz), 8.09 (dd, 1H, J=6.8, 2.4 Hz),8.03 (dd, 1H, J=13.2, 2.4 Hz), 7.90 (d, 1H, J=6.4 Hz), 7.56-7.51 (m,3H), 7.44 (t, 1H, J=8.8 Hz), 7.39-7.35 (m, 2H), 6.92 (d, 1H, J=6.4 Hz),6.68 (t, 1H, J=7.2 Hz), 3.33 (s, 2H), 3.10 (s, 2H), 2.77 (s, 3H), 2.76(s, 3H), 1.07 (s, 6H); MS (ESI⁺) m/z 548.34 (M+H)⁺.

Example 125

N-(4-(3-(2-Amino-3-hydroxypropylamino)pyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide,hydrochloride salt

Prepared in a similar manner as Example 121 to give the HCl salt of thetitle compound (65%) as a white solid. ¹H NMR (DMSO-d₆) δ 12.10 (s, 1H),8.52 (dd, 1H, J=7.2, 2 Hz), 8.30 (s, 1H), 8.09 (dd, 1H, J=6.8, 2.4 Hz),8.03 (dd, 1H, J=12.8, 2 Hz), 7.96 (d, 1H, J=6.4 Hz), 7.56-7.52 (m, 3H),7.43-7.35 (m, 3H), 6.93 (d, 1H, J=6 Hz), 6.68 (t, 1H, J=7.2 Hz),3.65-3.56 (m, 2H), 3.48-3.45 (m, 3H); MS (ESI⁺) m/z 508.27 (M+H)⁺.

Example 126

1-(4-(2-Amino-3-(hydroxymethyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,hydrochloride salt

A) tert-Butyl 4-chloro-3-formylpyridin-2-ylcarbamate

To (4-chloro-pyridin-2-yl)-carbamic acid tert-butyl ester (CB Researchand Development Inc., 2.0 g, 8.75 mmol) in THF (18 mL) under nitrogen at−78° C., was added n-BuLi (13.7 mL, 21.9 mmol, 1.6 M in hexanes)dropwise. After stirring at −78° C. for 45 min, a solution of DMF (1.93mL) in THF (2 mL) was added dropwise. The reaction was stirred at −78°C. for 30 min and was then allowed to warm slowly to room temperature.The reaction was quenched with 1N aq HCl solution and then basified withsaturated aqueous sodium bicarbonate solution (50 mL) and extracted withethyl acetate (3×50 mL). The combined organic extracts were dried overanhydrous Na₂SO₄ and concentrated in vacuo. The crude product waspurified by flash column chromatography on silica gel (EtOAc) to affordthe title compound (0.95 g, 42%) as a white solid. ¹H NMR (DMSO-d₆) δ10.44 (s, 1H), 10.13 (s, 1H), 8.47 (d, 1H, J=5.2 Hz), 7.40 (d, 1H, J=5.6Hz), 1.48 (s, 9H).

B) tert-Butyl 4-(2-fluoro-4-nitrophenoxy)-3-formylpyridin-2-ylcarbamate

To 2-fluoro-nitrophenol (Aldrich, 700 mg, 4.44 mmol) in DMF (5 mL) wasadded sodium hydride (60%, 180 mg, 4.44 mmol). After stirring at rt for5 min, a solution of tert-butyl 4-chloro-3-formylpyridin-2-ylcarbamate(0.95 g, 3.7 mmol) in 5 mL of DMF was added to the mixture. The reactionmixture was stirred at 60° C. for 20 h. After cooling to rt, thereaction was diluted with EtOAc (50 mL), washed with 10% aqueous lithiumchloride solution (2×40 mL) followed by saturated aqueous sodiumbicarbonate solution (40 mL), dried over anhydrous Na₂SO₄, andconcentrated in vacuo. The crude product was purified by flashchromatography on silica gel (50% EtOAc/hexanes) to give the titlecompound (1.0 g, 72%) as a yellow oil. ¹H NMR (CD₃OD) δ 10.59 (s, 1H),8.37-8.25 (m, 2H), 7.67 (t, 1H, J=7.6 Hz), 6.60 (d, 1H, J=6 Hz), 1.59(s, 9H).

C) tert-Butyl4-(2-fluoro-4-nitrophenoxy)-3-(hydroxymethyl)pyridin-2-ylcarbamate

To tert-butyl 4-(2-fluoro-4-nitrophenoxy)-3-formylpyridin-2-ylcarbamate(75 mg, 0.2 mmol) in methanol (1 mL) at 0° C. was added sodiumborohydride (7.6 mg, 0.20 mmol). After stirring at 0° C. for 30 min, thereaction was quenched with saturated aqueous ammonium chloride solution(1 mL). The reaction was diluted with EtOAc (5 mL) and the layers wereseparated. The organic layer was dried over anhydrous Na₂SO₄ andconcentrated in vacuo to give the title compound (65 mg, 86%) as a whitesolid which was used without further purification. ¹H NMR (CD₃OD) δ 8.28(dd, 1H, J=10.4, 2.8 Hz), 8.22-8.18 (m, 2H), 7.45 (t, 1H, J=8.4 Hz),6.68 (d, 1H, J=6 Hz), 4.81 (s, 2H), 1.57 (s, 9H); MS (ESI⁺) m/z 380.27(M+H)⁺.

D) tert-Butyl4-(4-amino-2-fluorophenoxy)-3-(hydroxymethyl)pyridin-2-ylcarbamate

Prepared in a similar manner as Step C of Example 59 to give the titlecompound as a white solid. ¹H NMR (CD₃OD) δ 8.14 (d, 1H, J=6 Hz), 6.97(t, 1H, J=8.8 Hz), 6.62-6.54 (m, 2H), 6.46 (d, 1H, J=6.4 Hz), 4.64 (s,2H), 1.55 (s, 9H); MS (ESI⁺) m/z 350.11 (M+H)⁺.

E)1-(4-(2-Amino-3-(hydroxymethyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,hydrochloride salt

Prepared in a similar manner as Step C of Example 59 to give the HClsalt of the title compound as a white solid. ¹H NMR (DMSO-d₆) δ 10.99(s, 1H), 10.56 (s, 1H), 7.82 (d, 1H, J=7.2 Hz), 7.74 (dd, 1H, J=13.6,2.8 Hz), 7.31-26 (m, 3H), 7.19-7.02 (m, 3H), 6.16 (d, 1H, J=7.2 Hz),4.57 (s, 2H), 3.69 (s, 2H); MS (ESI⁺) m/z 429.16 (M+H)⁺.

Example 127

1-(4-(2-Amino-3-((methylamino)methyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,hydrochloride salt

A) tert-Butyl(2-bis-BOC-amino-4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)methyl(methyl)carbamate

To tert-butyl 4-(2-fluoro-4-nitrophenoxy)-3-formylpyridin-2-ylcarbamate(Compound B of Example 126, 75 mg, 0.2 mmol) in dichloroethane (1 mL) at0° C. was added methylamine (240 μL, 0.24 mmol, 2M in THF), acetic acid(14 μL, 0.24 mmol), followed by sodium triacetoxyborohydride (400 mg,1.89 mmol). After stirring at rt for 16 h, the reaction mixture wasdiluted with EtOAc (5 mL), washed with saturated aqueous sodiumbicarbonate solution (5 mL), dried over anhydrous Na₂SO₄, andconcentrated in vacuo. The crude product was purified by flash columnchromatography on silica gel (20% MeOH/EtOAc) to give tert-butyl4-(2-fluoro-4-nitrophenoxy)-3-((methylamino)methyl)pyridin-2-ylcarbamate(37 mg, 47%) as a yellow oil.

To tert-butyl4-(2-fluoro-4-nitrophenoxy)-3-((methylamino)methyl)pyridin-2-ylcarbamate(48 mg, 0.122 mmol) and DMAP (16 mg, 0.134 mmol) in dichloromethane (1mL) was added di-tert-butyl dicarbonate (Aldrich, 32 mg, 0.15 mmol).After stirring at rt 30 min, a mixture of bis- and tris-BOC material(2:1) was observed. An additional portion of DMAP and di-tert-butyldicarbonate was added. After stirring at rt for 30 min, the reaction waspurified directly by flash column chromatography on silica gel (EtOAc)to give the title compound (44 mg, 61%) as a yellow oil. ¹H NMR (CD₃OD)δ 8.50 (d, 1H, J=5.2 Hz), 8.15-7.97 (m, 2H), 7.43 (d, 1H, J=5.6 Hz),7.07 (t, 1H, J=8.4 Hz), 4.64 (s, 2H), 2.83 (s, 3H), 1.44 (s, 27H); MS(ESI⁺) m/z 593.34 (M+H)⁺.

B)1-(4-(2-Amino-3-((methylamino)methyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,hydrochloride salt

Prepared in a similar manner as Step C of Example 59 to give the HClsalt of the title compound (60%) as a white solid. ¹H NMR (DMSO-d₆) δ10.88 (s, 1H), 10.35 (s, 1H), 7.45-7.42 (m, 1H), 7.30 (m, 3H), 7.11-7.07(m, 4H), 6.52 (d, 1H, J=7.2 Hz), 4.02 (s, 2H), 3.66 (s, 2H), 2.54 (s,3H); MS (ESI⁺) m/z 442.30 (M+H)⁺.

Example 128

1-(4-(2-Amino-3-((2-hydroxyethylamino)methyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,trifluoroacetic acid salt

A) tert-Butyl(2-BOC-amino-4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)methyl(2-hydroxyethyl)carbamate

Prepared in a similar manner as Step A of Example 127 to give the titlecompound (14%) as a yellow oil. ¹H NMR (CD₃OD) δ 8.30 (dd, 1H, J=10.4,2.8 Hz), 8.23-8.20 (m, 2H), 7.52 (t, 1H, J=8.4 Hz), 6.64 (d, 1H, J=7.2Hz), 4.71 (s, 2H), 3.65 (t, 2H, J=6 Hz), 3.40 (m, 2H), 1.57 (s, 18H); MS(ESI⁺) m/z 523.32 (M+H)⁺.

B)1-(4-(2-Amino-3-((2-hydroxyethylamino)methyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,trifluoroacetic acid salt

Prepared in a similar manner as Step C of Example 59 to give the TFAsalt of the title compound (45%) as a white solid. ¹H NMR (DMSO-d₆) δ11.12 (s, 1H), 10.69 (s, 1H), 8.01 (d, 1H, J=6.8 Hz), 7.87 (dd, 1H,J=12.8, 2.4 Hz), 7.53-7.40 (m, 4H), 7.26-7.20 (m, 2H), 6.68 (d, 1H,J=7.2 Hz), 4.34 (s, 2H), 3.81 (s, 2H), 3.75 (t, 2H, J=7.2 Hz), 3.18 (m,2H); MS (ESI⁺) m/z 472.24 (M+H)⁺.

Example 129

N-(4-(2-Amino-3-((2-aminoethylamino)methyl)pyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide,trifluoroacetic acid salt

A) tert-Butyl(2-BOC-amino-4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)methyl(2-BOC-aminoethyl)carbamate

Prepared in a similar manner as Step A of Example 127 to give the titlecompound (19%) as a yellow oil. ¹H NMR (CD₃OD) δ 8.30 (dd, 1H, J=10, 2.4Hz), 8.23-8.20 (m, 2H), 7.52 (t, 1H, J=8.4 Hz), 6.61 (d, 1H, J=7.2 Hz),4.65 (s, 2H), 3.39 (m, 2H), 3.25 (m, 2H), 1.61 (s, 27H); MS (ESI⁺) m/z622.47 (M+H)⁺.

B)N-(4-(2-Amino-3-((2-aminoethylamino)methyl)pyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide,trifluoroacetic acid salt

The nitro group was reduced in a similar manner as Step C of Example 59and then the amide was formed in a manner similar to Example 62 to givethe TFA salt of the title compound (28%) as a white solid. ¹H NMR(DMSO-d₆) δ 12.09 (s, 1H), 8.52 (dd, 1H, J=7.2, 2 Hz), 8.09 (dd, 1H,J=6.4, 2 Hz), 7.99 (dd, 1H, J=12.8, 2.4 Hz), 7.89 (d, 1H, J=6.4 Hz),7.56-7.52 (m, 2H), 7.49-7.47 (m, 1H), 7.39-7.33 (m, 3H), 6.68 (t, 1H,J=7.2 Hz), 6.07 (d, 1H, J=7.2 Hz), 4.25 (s, 2H), 3.20 (m, 2H), 3.08 (m,2H); MS (ESI⁺) m/z 507.23 (M+H)⁺.

Example 130

N-(4-(2-Amino-3-(hydroxymethyl)pyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide,trifluoroacetic acid salt

A) tert-Butyl3-((tert-butyldimethylsilyloxy)methyl)-4-(2-fluoro-4-nitrophenoxy)pyridin-2-ylcarbamate

To tert-butyl4-(2-fluoro-4-nitrophenoxy)-3-(hydroxymethyl)pyridin-2-ylcarbamate(Compound C of Example 126, 100 mg, 0.26 mmol) in dichloromethane (3 mL)was added imidazole (21 mg, 0.31 mmol) followed bytert-butyldimethylsilyl chloride (40 mg, 0.26 mmol). After stirring atrt for 1 h, a second equivalent of tert-butyldimethylsilyl chloride (40mg, 0.26 mmol) was added. The reaction was stirred at rt for 3 h and wasthen diluted with dichloromethane (10 mL), washed with water (10 mL),dried over anhydrous Na₂SO₄, and concentrated in vacuo. The crudeproduct was purified by flash column chromatography on silica gel (50%EtOAc/hexanes) to give the title compound (102 mg, 79%) as a whitesolid. ¹H NMR (CD₃OD) δ 8.16 (dd, 1H, J=10.4, 2.8 Hz), 8.09-8.05 (m,2H), 7.29 (t, 1H, J=8.4 Hz), 6.53 (d, 1H, J=5.6 Hz), 4.84 (s, 2H), 1.43(s, 9H), 0.84 (s, 9H), 0.00 (s, 6H); MS (ESI⁺) m/z 494.29 (M+H)⁺.

B) tert-Butyl4-(4-amino-2-fluorophenoxy)-3-((tert-butyldimethylsilyloxy)-methyl)pyridin-2-ylcarbamate

Prepared in a similar manner as Step C of Example 59 give the titlecompound (95 mg, 98%) as a yellow oil. ¹H NMR (CD₃OD) δ 7.90 (d, 1H, J=6Hz), 6.76 (t, 1H, J=8.8 Hz), 6.43 (dd, 1H, J=12.8, 2.8 Hz), 6.39-6.37(m, 1H), 6.21 (d, 1H, J=5.6 Hz), 4.85 (s, 2H), 1.39 (s, 9H), 0.81 (s,9H), 0.01 (s, 6H); MS (ESI⁺) m/z 464.34 (M+H)⁺.

C) tert-Butyl3-((tert-butyldimethylsilyloxy)methyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)pyridin-2-ylcarbamate

Prepared in a manner similar to that of Example 62 to give the titlecompound (86%) as a colorless oil. ¹H NMR (CD₃OD) δ 8.51 (dd, 1H, J=7.6,2.4 Hz), 7.93 (d, 1H, J=6 Hz), 7.84-7.80 (m, 2H), 7.40-7.37 (m, 2H),7.21-7.15 (m, 3H), 7.06 (t, 1H, J=8.8 Hz), 6.57 (t, 1H, J=6.8 Hz), 6.26(d, 1H, J=5.6 Hz), 4.86 (s, 2H), 1.40 (s, 9H), 0.82 (s, 9H), 0.00 (s,6H); MS (ESI⁺) m/z 679.34 (M+H)⁺.

D) tert-Butyl4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)-3-(hydroxymethyl)pyridin-2-ylcarbamate

To tert-Butyl3-((tert-butyldimethylsilyloxy)methyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)pyridin-2-ylcarbamate(119 mg, 0.176 mmol) in THF (2 mL) at rt was added tetrabutylammoniumfluoride (260 μL, 0.264 mmol, 1 M in THF). After stirring at rt for 30min, the reaction was diluted with ethyl acetate (20 mL), washed withwater followed by brine (10 mL each), dried over anhydrous MgSO₄, andconcentrated in vacuo. The crude product was purified by flash columnchromatography on silica gel (5% MeOH/EtOAc) to give the title compound(66 mg, 66%) as a yellow oil. ¹H NMR (CD₃OD) δ 8.62 (dd, 1H, J=7.2, 2Hz), 8.04 (d, 1H, J=6 Hz), 7.94-7.90 (m, 2H), 7.50-7.46 (m, 2H),7.33-7.25 (m, 3H), 7.20 (t, 1H, J=8.8 Hz), 6.67 (t, 1H, J=6.8 Hz), 6.40(d, 1H, J=5.2 Hz), 4.78 (s, 2H), 1.49 (s, 9H); MS (ESI⁺) m/z 565.17(M+H)⁺.

E)N-(4-(2-Amino-3-(hydroxymethyl)pyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide,trifluoroacetic acid salt

To tert-butyl4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)-3-(hydroxymethyl)pyridin-2-ylcarbamate(33 mg 0.058 mmol) in THF (2 mL) at rt was added 4N HCl in dioxane (10mL). After stirring at rt for 8 h, the reaction was concentrated invacuo. The resulting crude product was purified by prep HPLC. Theappropriate fractions were concentrated and toluene was added (2×3 mL)and the resulting mixture was concentrated again. The residue waslyophilized from acetonitrile (1 mL)/water (3 mL) to give the TFA saltof the title compound (14 mg, 42%) as a white solid. ¹H NMR (DMSO-d₆) δ12.08 (s, 1H), 8.52 (dd, 1H, J=7.2, 2 Hz), 8.09 (dd, 1H, J=6.8, 2 Hz),7.99 (dd, 1H, J=12.8, 2.4 Hz), 7.81 (d, 1H, J=7.2 Hz), 7.56-7.52 (m,2H), 7.48-7.46 (m, 1H), 7.39-7.34 (m, 2H), 7.30 (t, 1H, J=9.2 Hz), 6.67(t, 1H, J=7.2 Hz), 6.21 (d, 1H, J=7.2 Hz), 4.58 (s, 2H); MS (ESI⁺) m/z465.17 (M+H)⁺.

Example 131

1-(4-(2-Amino-3-(2-(pyridin-2-yl)ethynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,dihydrochloride salt

A)4-(2-Fluoro-4-nitrophenoxy)-3-(2-(pyridin-2-yl)ethynyl)pyridin-2-amine

A solution of 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridin-2-amine(Compound C of Example 34, 100 mg, 0.27 mmol), 2-ethynylpyridine(Aldrich, 56 μL, 0.54 mmol), Et₃N (2 mL), and THF (2 mL) was degassed byvacuum/argon purge and then treated with CuI (6 mg, 0.032 mmol) and(Ph₃P)₄Pd (20 mg, 0.017 mmol). The reaction mixture was heated at 60° C.for 45 min, cooled to RT and diluted with EtOAc. The mixture was washedwith saturated aqueous NaHCO₃ solution, brine, dried (MgSO₄) andconcentrated in vacuo. The crude product was purified by flashchromatography on SiO₂ using 0-1.5% MeOH/CH₂Cl₂ to give the titlecompound (55 mg, 57%) as an olive green solid. ¹H NMR (DMSO-d₆) δ 8.53(d, 1H, J=5.1 Hz), 8.42-8.37 (m, 1H), 8.19-8.12 (m, 1H), 7.96 (d, 1H,J=5.6 Hz), 7.85-7.78 (m, 1H), 7.71 (d, 1H, J=7.6 Hz), 7.52 (t, 1H, J=8.6Hz), 7.36 (ddd, 1H, J=7.6, 5.1, 1.0 Hz), 6.71 (s, 2H), 6.21 (d, 1H,J=5.6 Hz); MS (ESI⁺): m/z 351.25 (M+H)⁺.

B)4-(4-Amino-2-fluorophenoxy)-3-(2-(pyridin-2-yl)ethynyl)pyridin-2-amine

The title compound was prepared from the reduction of4-(2-fluoro-4-nitrophenoxy)-3-(2-(pyridin-2-yl)ethynyl)pyridin-2-amine(35 mg, 0.10 mmol) using zinc dust (65 mg, 1.0 mmol) and NH₄Cl (53 mg,1.0 mmol) in the same manner as Step C of Example 11. This gave thetitle compound (25 mg, 78%) as brown oil. MS (ESI⁺): m/z 321.25 (M+H)⁺.

C)1-(4-(2-Amino-3-(2-(pyridin-2-yl)ethynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,dihydrochloride salt

The title compound was prepared from4-(4-amino-2-fluorophenoxy)-3-(2-(pyridin-2-yl)ethynyl)pyridin-2-amine(25 mg, 0.078 mmol) and a 0.3 M solution of 2-(4-fluorophenyl)acetylisocyanate in toluene (Compound D of Example 11, 0.26 mL, 0.078 mmol) inthe same manner as Step E of Example 11. The crude product was preparedby preparative HPLC (Column B). The TFA salt was converted to thehydrochloride in the same manner as in Step E of Example 36 to give thetitle compound (18 mg, 40%) as a brown solid. ¹H NMR (DMSO-d₆) δ 11.06(s, 1H), 10.63 (s, 1H), 8.62 (d, 1H, J=4.6 Hz), 8.23 (s, 1H), 7.99 (d,1H, J=7.1 Hz), 7.94-7.84 (m, 3H), 7.87-7.76 (m, 1H), 7.51-7.42 (m, 3H),7.39-7.32 (m, 2H), 7.21-7.13 (m, 2H), 6.30 (d, 1H, J=7.1 Hz), 3.74 (s,2H) MS (ESI⁺): m/z 498.11 (M+H)⁺.

Example 132

N-(4-(2-Amino-3-(4-(2-amino-2-oxoethyl)phenyl)pyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide,hydrochloride salt

The title compound was prepared from2-(4-(2-amino-4-(4-amino-2-fluorophenoxy)pyridin-3-yl)phenyl)acetamide(Compound C of Example 78, 18 mg, 0.05 mmol) and1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (CompoundB of Example 101, 11 mg, 0.05 mmol) in the same manner as Example 62.The crude product was prepared by preparative HPLC (Column B) followedby conversion of the TFA salt to the hydrochloride salt (15 mg, 50%). ¹HNMR (DMSO-d₆) δ 12.11 (s, 1H), 8.58-8.54 (m, 1H), 8.13 (dd, 1H, J=6.6,2.2 Hz), 8.00 (dd, 1H, J=12.6, 2.2 Hz), 7.96 (d, 1H, J=7.7 Hz), 7.59(dd, 2H, J=8.8, 4.9 Hz), 7.47-7.41 (m, 6H), 7.40-7.35 (m, 3H), 6.94 (s,1H), 6.72 (t, 1H, J=7.1 Hz), 6.38 (d, 1H, J=7.1 Hz), 3.44 (s, 2H); MS(ESI⁺): m/z 568.23 (M+H)⁺.

Example 133

1-(4-(2-Amino-3-(2-(5-aminopyridin-2-yl)ethynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,dihydrochloride salt

A) 6-(2-(Trimethylsilyl)ethynyl)pyridin-3-amine

A mixture of 3-amino-6-bromopyridine (Alfa Aesar, 1.0 g, 5.8 mmol),ethynyl trimethylsilane (1.7 mL, 17.3 mmol), CH₃CN (3 mL), DMF (2 mL)and Et₃N (2 mL) was treated with CuI (60 mg, 0.32 mmol) and (Ph₃P)₄Pd(114 mg, 0.10 mmol) and the mixture stirred at 45° C. for 1.5 h. Moreethynyltrimethylsilane (1.7 mL, 17.3 mmol) was added to the reaction andthe mixture was stirred for 2 h. The mixture was concentrated in vacuoand the residue partitioned between EtOAc and saturated aqueous NaHCO₃solution. The EtOAc phase was washed with brine, dried (MgSO₄) andconcentrated in vacuo. The crude product was purified by flashchromatography on SiO₂ using 0-6% EtOAc/hexanes to give the titlecompound (0.75 g, 68%) as a brown solid. ¹H NMR (DMSO-d₆) δ 7.85 (s,1H), 7.15 (d, 1H, J=8.1 Hz), 6.81 (d, 1H, J=8.1 Hz), 5.76 (s, 2H), 0.19(s, 9H); MS (ESI⁺): m/z 191.20 (M+H)⁺.

B) tert-Butyl 6-(2-(trimethylsilyl)ethynyl)pyridin-3-ylcarbamate

A solution 6-(2-(trimethylsilyl)ethynyl)pyridin-3-amine (0.5 g, 2.6mmol) in THF was cooled to −50° C. and treated dropwise with 1.0 MNaHMDS in THF (5.3 mL, 5.5 mmol). The mixture was warmed to −20° C.,treated with BOC anhydride in one portion and allowed to warm to RT over25 min. The mixture was partitioned between EtOAc and saturated aqueousNaHCO₃ solution and the EtOAc phase was separated and washed with brine.The EtOAc solution was dried (MgSO₄) and concentrated in vacuo. Thecrude product was purified by flash chromatography on SiO₂ using 0-25%EtOAc/hexanes to give the product (0.5 g, 67%) as a white solid. ¹H NMR(DMSO-d₆) δ 9.80 (s, 1H), 8.58 (d, 1H, J=2.0 Hz), 7.86 (dd, J=8.6, 2.5Hz, 1H), 7.44 (d, 1H, J=8.6 Hz), 1.47 (s, 9H), 0.22 (s, 9H); MS (ESI⁺):m/z 291.34 (M+H)⁺.

C) tert-Butyl 6-ethynylpyridin-3-ylcarbamate

A solution of tert-butyl6-(2-(trimethylsilyl)ethynyl)pyridin-3-ylcarbamate (62 mg, 0.21 mmol) inTHF (5 mL) was cooled to −15° C. and treated with 1.0 Mtetrabutylammonium fluoride (Aldrich, 0.25 mL, 0.25 mmol) and stirredfor 40 min. The mixture was concentrated in vacuo and partitionedbetween EtOAc and saturated aqueous NaHCO₃ solution. The EtOAc phase waswashed with brine, dried (MgSO₄) and concentrated in vacuo to give thetitle compound (45 mg, 100%) as an off-white solid. ¹H NMR (DMSO-d₆) δ9.78 (s, 1H), 8.58 (d, 1H, J=2.5 Hz), 7.92-7.84 (m, 1H), 7.46 (d, 1H,J=8.6 Hz), 4.17 (s, 1H), 1.47 (s, 9H); MS (ESI⁺): m/z 219.20 (M+H)⁺.

D) tert-Butyl6-(2-(2-amino-4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)ethynyl)pyridin-3-ylcarbamate

The title compound was prepared from tert-butyl6-ethynylpyridin-3-ylcarbamate and4-(2-fluoro-4-nitrophenoxy)-3-iodopyridin-2-amine (Compound C of Example34) in the same manner as Step A of Example 46 in 44% yield. ¹H NMR(DMSO-d₆) δ 9.77 (s, 1H), 8.56 (s, 1H), 8.40-8.36 (m, 1H), 8.14 (d, 1H,J=8.8 Hz), 7.94 (d, 1H, J=5.5 Hz), 7.89 (d, 1H, J=8.2 Hz), 7.59 (d, 1H,J=8.8 Hz), 7.53-7.47 (m, 1H), 6.63 (br s, 2H), 6.21 (d, 1H, J=6.0 Hz),1.47 (s, 9H); MS (ESI⁺): m/z 466.22 (M+H)⁺.

E) tert-Butyl6-(2-(2-amino-4-(4-amino-2-fluorophenoxy)pyridin-3-yl)ethynyl)pyridin-3-ylcarbamate

The title compound was prepared from tert-butyl6-(2-(2-amino-4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)ethynyl)pyridin-3-ylcarbamatein the same manner as Step C of Example 11 in quantitative yield. MS(ESI⁺): m/z 436.29 (M+H)⁺.

F) tert-Butyl6-(2-(2-amino-4-(2-fluoro-4-(3-(2-(4-fluorophenyl)acetyl)ureido)phenoxy)pyridin-3-yl)ethynyl)pyridin-3-ylcarbamate

The title compound was prepared from tert-butyl6-(2-(2-amino-4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)ethynyl)pyridin-3-ylcarbamatein the same manner as Step E of Example 11 in 80% yield. ¹H NMR(DMSO-d₆) δ 11.02 (s, 1H), 10.56 (s, 1H), 9.78 (s, 1H), 8.59 (d, 1H,J=2.5 Hz), 7.91 (dd, 1H, J=8.6, 2.5 Hz), 7.81 (d, 1H, J=5.6 Hz), 7.75(dd, 1H, J=12.7, 2.5 Hz), 7.68 (d, 1H, J=8.6 Hz,), 7.44-7.27 (m, 5H),7.19-7.13 (m, 2H), 6.47 (s, 2H), 5.86-5.81 (m, 1H), 1.48 (s, 9H); MS(ESI⁺): m/z 615.34 (M+H)⁺.

G)1-(4-(2-Amino-3-(2-(5-aminopyridin-2-yl)ethynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,dihydrochloride salt

A solution of tert-butyl6-(2-(2-amino-4-(2-fluoro-4-(3-(2-(4-fluorophenyl)acetyl)ureido)phenoxy)pyridin-3-yl)ethynyl)pyridin-3-ylcarbamate(23 mg, 0.037 mmol) in CH₂Cl₂ (2 mL) and treated with TFA (0.5 mL) andstirred at RT for 1 h. The mixture was concentrated in vacuo and thecrude product purified by preparative HPLC (Column B) and converted toits hydrochloride salt (11 mg, 52%) in the same manner as Step E ofExample 36. ¹H NMR (DMSO-d₆) δ 11.05 (s, 1H), 10.62 (s, 1H), 8.05 (s,1H), 7.97 (d, 1H, J=2.7 Hz), 7.94 (d, 1H, J=7.1 Hz), 7.82 (d, 1H, J=12.1Hz), 7.66 (d, 1H, J=8.8 Hz), 7.45-7.45 (m, 2H), 7.35 (dd, 2H, J=8.2, 5.5Hz), 7.20 (d, 1H, J=6.6 Hz), 7.16 (t, 2H, J=8.8 Hz), 6.24 (d, 1H, J=6.6Hz), 3.74 (s, 2H); MS (ESI⁺): m/z 515.19 (M+H)⁺.

Example 134

N-(4-(2-Amino-3-(3-((3R,4R)-3-hydroxy-4-(pyrrolidin-1-yl)pyrrolidin-1-yl)-3-methylbut-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide,trihydrochloride salt

A) (3R,4R)-1-(2-Methylbut-3-yn-2-yl)-4-(pyrrolidin-1-yl)pyrrolidin-3-ol

A mixture of (3R,4R)-4-(pyrrolidin-1-yl)pyrrolidin-3-ol (Lexicon Pharma,1.56 g, 10.0 mmol) and 3-chloro-3-methyl-1-butyne (GFS Chmeical, Inc.,1.36 g, 13.2 mmol), THF (15 mL) and Et₃N (13.3 mmol) was treated withCuI (77 mg, 0.78 mmol). An exothermic reaction ensued with concomitantformation of a precipitate. After stirring at RT for 15 h, the mixturewas concentrated in vacuo and partitioned between EtOAc and saturatedaqueous NaHCO₃ solution. The aqueous phase was extracted twice withEtOAc and the combined EtOAc phases were dried (MgSO₄) and concentratedto give a light brown solid (1.0 g, 45%). ¹H NMR (CDCl₃) δ 4.20 (br s,1H), 3.13-3.04 (m, 1H), 2.95 (dd, 1H, J=10.1, 6.6 Hz), 2.77 (dd, 1H,J=10.1, 2.6 Hz), 2.64 (m, 3H), 2.61 (m, 2H), 2.55-2.46 (m, 1H), 2.26 (s,1H), 1.85-1.74 (m, 4H), 1.38 (s, 3H), 1.36 (s, 3H); MS (ESI⁺): m/z223.29 (M+H)⁺.

B)(3R,4R)-1-(4-(2-Amino-4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)-2-methylbut-3-yn-2-yl)-4-(pyrrolidin-1-yl)pyrrolidin-3-ol

The title compound was prepared from(3R,4R)-1-(2-methylbut-3-yn-2-yl)-4-(pyrrolidin-1-yl)pyrrolidin-3-ol and4-(2-fluoro-4-nitrophenoxy)-3-iodopyridin-2-amine (Compound C of Example34) in the same manner as Step D of Example 35 in 57% yield. ¹H NMR(CDCl₃) δ 8.10 (dd, 1H, J=10.2, 2.5 Hz), 8.03 (d, 1H, J=9.2 Hz), 7.99(d, 1H, J=5.6 Hz), 7.13-7.06 (m, 1H), 6.26 (d, 1H, J=6.1 Hz), 5.18 (brs, 2H), 4.21 (m, 1H), 3.10-2.99 (m, 1H), 2.96 (s, 1H), 2.70 (dd, 2H,J=9.7, 3.1 Hz), 2.66-1.15 (m, 2H), 1.87-1.76 (m, 5H), 133-1.32 (m, 2H),1.32 (m, 3H); 1.34 (m, 3H); MS (ESI⁺): m/z 470.20 (M+H)⁺.

C)(3R,4R)-1-(4-(2-Amino-4-(4-amino-2-fluorophenoxy)pyridin-3-yl)-2-methylbut-3-yn-2-yl)-4-(pyrrolidin-1-yl)pyrrolidin-3-ol

The title compound was prepared from(3R,4R)-1-(4-(2-amino-4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)-2-methylbut-3-yn-2-yl)-4-(pyrrolidin-1-yl)pyrrolidin-3-olin the same manner as Step C of Example 11 in 95% yield. MS (ESI⁺): m/z440.37 (M+H)⁺.

D)N-(4-(2-Amino-3-(3-((3R,4R)-3-hydroxy-4-(pyrrolidin-1-yl)pyrrolidin-1-yl)-3-methylbut-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide,trihydrochloride salt

The title compound was prepared from(3R,4R)-1-(4-(2-amino-4-(4-amino-2-fluorophenoxy)pyridin-3-yl)-2-methylbut-3-yn-2-yl)-4-(pyrrolidin-1-yl)pyrrolidin-3-oland 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid(Compound B of Example 101) in the same manner as Example 62 in 50%yield. ¹H NMR (DMSO-d₆) δ 12.14 (s, 1H), 8.62-8.54 (m, 1H), 8.14 (dd,3H, J=6.6, 2.0 Hz), 8.05 (d, 1H, J=13.2 Hz), 7.99 (d, 1H, J=7.1 Hz),7.62-7.51 (m, 5H), 7.42 (t, 2H, J=8.6 Hz), 6.78-6.70 (m, 1H), 6.32 (d,1H, J=7.1 Hz), 4.65 (br s, 1H), 3.94-3.84 (m, 1H), 3.71 (d, 2H, J=16.8Hz), 3.60 (m, 2H), 3.52 (m, 1H), 3.22-3.08 (m, 2H), 2.00-1.91 (m, 2H),1.88-1.78 (m, 2H), 1.70 (s, 6H); MS (ESI⁺): m/z 655.40 (M+H)⁺.

Example 135

1-(4-(2-Amino-3-(3-((3R,4R)-3-hydroxy-4-(pyrrolidin-1-yl)pyrrolidin-1-yl)-3-methylbut-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,trihydrochloride salt

The title compound was prepared form(3R,4R)-1-(4-(2-amino-4-(4-amino-2-fluorophenoxy)pyridin-3-yl)-2-methylbut-3-yn-2-yl)-4-(pyrrolidin-1-yl)pyrrolidin-3-olin 40% yield in the same manner as Step E of Example 11. ¹H NMR(DMSO-d₆) δ 11.06 (s, 1H), 10.62 (s, 1H), 7.97 (d, 2H, J=6.6 Hz), 7.80(d, 1H, J=11.7 Hz), 7.51-7.40 (m, 2H), 7.38-7.32 (m, 2H), 7.16 (t, 2H,J=8.6 Hz), 6.25 (d, 1H, J=6.6 Hz), 4.63-4.53 (m, 1H), 3.79-3.68 (m, 1H),3.74 (s, 2H), 3.68-3.56 (m, 2H), 3.51-3.43 (m, 2H), 3.08-2.99 (m, 4H),1.98-1.92 (m, 2H), 1.89-1.77 (m, 2H), 1.64 (s, 6H); MS (ESI⁺): m/z619.41 (M+H)⁺.

Example 136

1-(3-Fluoro-4-(3-(3-hydroxyprop-1-ynyl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea,hydrochloride salt

A) 3-(4-(2-Fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-yn-1-ol

The title compound was prepared from4-(2-fluoro-4-nitrophenoxy)-3-iodopyridine (Compound A of Example 33)and propargyl alcohol (Aldrich) in 77% yield in the same manner as StepA of Example 36. ¹H NMR (DMSO-d₆) δ 8.69 (s, 1H), 8.49 (d, 1H, J=5.6Hz), 8.43 (dd, 1H, J=10.7, 2.5 Hz), 8.17 (d, 1H, J=9.2 Hz), 7.57 (t, 1H,J=8.6 Hz), 7.04 (d, 1H, J=5.6 Hz), 5.40 (t, 1H, J=6.1 Hz), 4.28 (d, 2H,J=6.1 Hz); MS (ESI⁺): m/z 289.15 (M+H)⁺.

B) 3-(4-(4-Amino-2-fluorophenoxy)pyridin-3-yl)prop-2-yn-1-ol

The title compound was prepared in form3-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-yn-1-ol in 95% yieldin the same manner as Step C of Example 11. MS (ESI⁺): m/z 259.21(M+H)⁺.

C)1-(3-Fluoro-4-(3-(3-hydroxyprop-1-ynyl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea,hydrochloride salt

The title compound was prepared from3-(4-(4-amino-2-fluorophenoxy)pyridin-3-yl)prop-2-yn-1-ol in 36% yieldin the same manner as Step E of Example 11. ¹H NMR (DMSO-d₆) δ 11.06 (s,1H), 10.63 (s, 1H), 8.79 (s, 1H), 8.49 (d, 1H, J=6.1 Hz), 7.82 (d, 1H,J=12.2 Hz), 7.45-7.40 (m, 2H), 7.38-7.33 (m, 2H), 7.23-7.13 (m, 2H),6.89 (d, 1H, J=6.1 Hz), 4.37 (s, 2H), 3.74 (s, 2H); MS (ESI⁺): m/z438.23 (M+H)⁺.

Example 137

N-(4-(2-Amino-3-(3-aminoprop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide,dihydrochloride salt

A) tert-Butyl3-(2-amino-4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-ynylcarbamate

The title compound was prepared from N-Boc propargylamine (Compound A ofExample 42) and 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridin-2-amine(Compound C of Example 34) in the same manner as Step A of Example 42 in59% yield. ¹H NMR (DMSO-d₆) δ 8.35 (dd, 1H, J=10.7, 2.5 Hz), 8.12 (d,1H, J=9.2 Hz), 7.88 (d, 1H, J=5.6 Hz), 7.39 (t, 1H, J=8.6 Hz), 7.31 (t,1H, J=5.1 Hz), 6.53 (s, 2H), 6.15 (d, 1H, J=5.6 Hz), 3.92 (d, 2H, J=5.6Hz), 1.36 (s, 9H); MS (ESI⁺): m/z 403.34 (M+H)⁺.

B) tert-Butyl3-(2-amino-4-(4-amino-2-fluorophenoxy)pyridin-3-yl)prop-2-ynylcarbamate

The title compound was prepared from tert-butyl3-(2-amino-4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-ynylcarbamatein quantitative yield in the same manner as Step C of Example 11. MS(ESI⁺): m/z 373.35 (M+H)⁺.

C) tert-Butyl3-(2-amino-4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)pyridin-3-yl)prop-2-ynylcarbamate

The title compound was prepared from tert-butyl3-(2-amino-4-(4-amino-2-fluorophenoxy)pyridin-3-yl)prop-2-ynylcarbamateand 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid(Compound B of Example 101) in the same manner as Example 62 in 48%yield. ¹H NMR (DMSO-d₆) δ 12.07 (s, 1H), 8.57 (dd, 1H, J=7.1, 2.0 Hz),8.12 (dd, 1H, J=6.6, 2.0 Hz), 8.00-7.93 (m, 1H), 7.75 (d, 1H, J=6.1 Hz),7.61 (d, 2H, J=5.1 Hz), 7.59 (d, 1H, J=4.6 Hz), 7.48-7.37 (m, 4H),7.30-7.25 (m, 1H), 6.72 (t, 1H, J=7.1 Hz), 6.37 (br s, 1H), 5.80 (d, 1H,J=6.1 Hz), 4.00 (d, 2H, J=5.1 Hz), 1.38 (s, 9H); MS (ESI⁺): m/z 588.26(M+H)⁺.

D)N-(4-(2-Amino-3-(3-aminoprop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide,dihydrochloride salt

The title compound was prepared from tert-butyl3-(2-amino-4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)pyridin-3-yl)prop-2-ynylcarbamatein 80% yield in the same manner as Step E of Example 36. ¹H NMR(DMSO-d₆) δ 12.13 (s, 1H), 8.57 (dd, 1H, J=7.1, 2.0 Hz), 8.51 (s, 2H),8.14 (dd, 1H, J=6.6, 2.0 Hz), 8.11-8.02 (m, 1H), 7.98-7.90 (m, 1H), 7.60(dd, 2H, J=9.2, 5.1 Hz), 7.53 (d, 1H, J=9.2 Hz), 7.46-7.37 (m, 3H),6.76-6.71 (m, 1H), 6.20 (d, 1H, J=6.6 Hz), 4.11-4.04 (m, 2H); MS (ESI⁺):m/z 488.16 (M+H)⁺.

Example 138

1-(4-(2-Amino-3-(3-aminoprop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,dihydrochloride salt

A) tert-Butyl3-(2-amino-4-(2-fluoro-4-(3-(2-(4-fluorophenyl)acetyl)ureido)phenoxy)pyridin-3-yl)prop-2-ynylcarbamate

The title compound was prepared from tert-butyl3-(2-amino-4-(4-amino-2-fluorophenoxy)pyridin-3-yl)prop-2-ynylcarbamatein 38% yield in the same manner as Step E of Example 11. ¹H NMR(DMSO-d₆) δ 11.02 (s, 1H), 10.55 (s, 1H), 7.80-7.73-7.69 (m, 2H),7.38-7.29 (m, 3H), 7.33 (d, 1H, J=5.1 Hz), 7.30-7.21 (m, 1H), 7.21-7.13(m, 2H), 6.37 (br s, 1H), 5.76 (d, 1H, J=6.1 Hz), 4.00 (s, 2H), 3.73 (s,2H), 1.38 (s, 9H); MS (ESI⁺): m/z 552.24 (M+H)⁺.

B)1-(4-(2-Amino-3-(3-aminoprop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,dihydrochloride salt

The title compound was prepared from tert-butyl3-(2-amino-4-(2-fluoro-4-(3-(2-(4-fluorophenyl)acetyl)ureido)phenoxy)pyridin-3-yl)prop-2-ynylcarbamatein 65% yield in the same manner as Step E of Example 11. ¹H NMR(DMSO-d₆) δ 11.05 (s, 1H), 10.61 (s, 1H), 8.48 (br s, 3H), 7.90 (d, 1H,J=6.6 Hz), 7.84-7.76 (m, 2H), 7.45-7.39 (m, 1H), 7.39-7.32 (m, 3H),7.20-7.13 (m, 2H), 6.11 (d, 1H, J=6.1 Hz), 4.09-4.03 (m, 2H), 3.74 (s,2H); MS (ESI⁺): m/z 452.12 (M+H)⁺.

Example 139

1-(4-(2-Amino-3-(3-hydroxyprop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,hydrochloride salt

A) 3-(2-Amino-4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-yn-1-ol

The title compound was prepared from propargyl alcohol (Aldrich) and4-(2-fluoro-4-nitrophenoxy)-3-iodopyridin-2-amine (Compound C of Example34) in 46% in the same manner as Step A of Example 36. ¹H NMR (DMSO-d₆)δ 8.40-8.34 (m, 1H), 8.13 (d, 1H, J=8.6 Hz), 7.88 (d, 1H, J=5.6 Hz),7.42 (t, 1H, J=8.6 Hz), 6.49 (s, 2H), 6.14 (d, 1H, J=6.1 Hz), 5.26-5.20(m, 1H), 4.26 (d, 2H, J=6.1 Hz); MS (ESI⁺): m/z 304.23 (M+H)⁺.

B) 3-(2-Amino-4-(4-amino-2-fluorophenoxy)pyridin-3-yl)prop-2-yn-1-ol

The title compound was prepared form3-(2-amino-4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-yn-1-ol in 65%yield. MS (ESI⁺): m/z 274.21 (M+H)⁺.

C)1-(4-(2-Amino-3-(3-hydroxyprop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,hydrochloride salt

The title compound was prepared from3-(2-amino-4-(4-amino-2-fluorophenoxy)pyridin-3-yl)prop-2-yn-1-ol in 48%yield. ¹H NMR (DMSO-d₆) δ 11.05 (s, 1H), 10.60 (s, 1H), 7.86 (d, 1H,J=7.1 Hz), 7.83-7.77 (m, 1H), 7.44-7.37 (m, 2H), 7.37-7.32 (m, 3H),7.20-7.13 (m, 2H), 6.14 (d, J=6.6 Hz, 1H), 4.37 (s, 2H), 3.74 (s, 2H);MS (ESI⁺): m/z 453.28 (M+H)⁺.

Example 140

N-(4-(2-Amino-3-(3-(dimethylamino)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide,dihydrochloride salt

A)3-(3-(Dimethylamino)prop-1-ynyl)-4-(2-fluoro-4-nitrophenoxy)pyridin-2-amine

The title compound was prepared from 1-dimethylamin-2-propyne (Aldrich)and 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridin-2-amine (Compound C ofExample 34) in 64% yield in the same manner as Step A of Example 42. ¹HNMR (DMSO-d₆) δ 8.36 (dd, 1H, J=10.7, 2.5 Hz), 8.11 (d, 1H, J=8.6 Hz),7.93 (d, 1H, J=5.6 Hz), 7.30 (t, 1H, J=8.6 Hz), 6.43 (br s, 2H), 6.28(d, 1H, J=6.1 Hz), 3.41 (s, 2H), 2.05 (s, 6H); MS (ESI⁺): m/z 331.28(M+H)⁺.

B)4-(4-Amino-2-fluorophenoxy)-3-(3-(dimethylamino)prop-1-ynyl)pyridin-2-amine

The title compound was prepared from3-(3-(dimethylamino)prop-1-ynyl)-4-(2-fluoro-4-nitrophenoxy)pyridin-2-aminein 77% yield in the same manner as Step C of Example 11. MS (ESI⁺): m/z301.30 (M+H)⁺.

C)N-(4-(2-Amino-3-(3-(dimethylamino)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide,dihydrochloride salt

The title compound was prepared from4-(4-amino-2-fluorophenoxy)-3-(3-(dimethylamino)prop-1-ynyl)pyridin-2-amineand 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid(Compound B of Example 101) in the same manner as Example 62 in 71%yield. ¹H NMR (DMSO-d₆) δ 12.14 (s, 1H), 11.39 (s, 1H), 8.60-8.53 (m,1H), 8.33 (s, 1H), 8.14 (dd, 1H, J=6.6, 2.2 Hz), 8.05 (dd, 1H, J=12.7,2.2 Hz), 7.98 (d, 1H, J=7.0 Hz), 7.61 (d, 1H, J=5.3 Hz), 7.58 (d, 1H,J=4.8 Hz), 7.56-7.50 (m, 1H), 7.37-7.47 (m, 3H), 6.76-6.69 (m, 1H), 6.30(d, 1H, J=7.0 Hz), 4.39 (s, 2H), 2.84 (s, 6H); MS (ESI⁺): m/z 480.28(M+H)⁺.

Example 141

1-(4-(2-Amino-3-(3-(dimethylamino)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,dihydrochloride salt

The title compound was prepared from4-(4-amino-2-fluorophenoxy)-3-(3-(dimethylamino)prop-1-ynyl)pyridin-2-aminein a similar manner as Step E of Example 11 in 70% yield. ¹H NMR(DMSO-d₆) δ 11.46 (br s, 1H), 11.07 (s, 1H), 10.64 (s, 1H), 8.37 br (s,1H), 7.98 (t, 1H, J=7.5 Hz), 7.81 (d, 1H, J=13.6 Hz), 7.43-7.32 (m, 4H),7.20-7.09 (m, 2H), 6.27 (d, 1H, J=7.0 Hz), 4.38 (s, 2H), 3.75 (s, 2H),2.84 (s, 6H); MS (ESI⁺): m/z 516.31 (M+H)⁺.

Example 142

1-(4-(2-Aminopyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea,hydrochloride salt

A) 4-(4-Aminophenoxy)picolinamide

The title compound was prepared in a similar manner described in Step B′of Example 24, starting from 4-aminophenol. Yield: 85%. MS (ESI⁺) m/z230 (M+H)⁺.

B)1-(4-(2-Carbamoylpyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea

The title compound was prepared in a similar manner described in Step C′of Example 24. Yield: 95%. MS (ESI⁺) m/z 409 (M+H)⁺.

C)1-(4-(2-Aminopyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea,hydrochloride salt

The title compound was prepared in a similar manner described in Step D′of Example 24. Yield: 58%. ¹H NMR (DMSO-d₆) δ 12.86 (s, 1H), 10.97 (s,1H), 10.51 (s, 1H), 7.91 (d, 1H, J=6.0 Hz), 7.67 (d, 3H, J=9.0 Hz), 7.34(dd, 2H, J=9.0, 5.0 Hz), 7.21 (d, 2H, J=9.0 Hz), 7.16 (t, 2H, J=9.0 Hz),6.63 (dd, 1H, J=9.5, 2.0 Hz), 6.05 (d, 1H, J=2.0 Hz), 3.73 (s, 2H); MS(ESI⁺) m/z 381 (M+H)⁺.

Example 143

1-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-3-(2-(3-hydroxyphenyl)acetyl)urea

A) 2-(3-(Benzyloxy)phenyl)acetic acid

To a solution of 3-hydroxyphenylacetic acid (Acros, 3.04 g, 20 mmol) in20 mL of DMF were added K₂CO₃ (6.90 g, 50 mmol) and benzyl bromide (4.75mL, 40 mmol) at room temperature. The reaction mixture was stirred for24 h. The suspension was filtered and washed with diethyl ether. Thefiltrate was then washed with brine and dried over MgSO₄. Filtration,followed by concentration, provided the crude benzyl2-(3-(benzyloxy)phenyl)acetate which was used in the next step. MS(ESI⁺) m/z 355 (M+Na)⁺.

The crude benzyl 2-(3-(benzyloxy)phenyl)acetate was dissolved in amixture of MeOH (20 mL) and THF (50 mL). To this solution was added 40mL of 1N NaOH (40 mmol). The reaction mixture was stirred at roomtemperature for 2 h. The organic solvent was removed in vacuo. Theremaining aqueous solution was extracted with diethyl ether (2×50 mL).The aqueous solution was then acidified with 1N HCl (50 mL) and thetitle compound precipitated. The solid was collected by filtration (4.35g, 90% two steps). MS (ESI⁺) m/z 265 (M+Na)⁺.

B) 2-(3-(Benzyloxy)phenyl)acetyl isocyanate

To a solution of 2-(3-(benzyloxy)phenyl)acetic acid (484 mg, 2.0 mmol)in DCM (10 mL) at room temperature was added 1 drop of DMF and thionylchloride (0.30 mL, 4 mmol). The reaction mixture was stirred at roomtemperature for 1 h and then at 50° C. for 0.5 h. The mixture was cooledand the solvent was removed in vacuo. The residue was dissolved in 5 mLof toluene and AgOCN (600 mg, 4.0 mmol) was added. The suspension wasstirred for 0.5 h and it was filtered to provide a solution of2-(3-(benzyloxy)phenyl)acetyl isocyanate in toluene (0.40 M).

C)1-(2-(3-(Benzyloxy)phenyl)acetyl)-3-(4-(2-carbamoylpyridin-4-yloxy)-3-fluorophenyl)urea

The title compound was prepared in a similar manner described in Step C′of Example 24, using the solution of Step B of this Example. Yield: 63%.MS (ESI⁺) m/z 515 (M+H)⁺.

D)1-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-3-(2-(3-(benzyloxy)phenyl)acetyl)urea

The title compound was prepared in a similar manner described in Step D′of Example 24. Yield: 61%. MS (ESI⁺) m/z 487 (M+H)⁺.

E)1-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-3-(2-(3-hydroxyphenyl)acetyl)urea

To a solution of1-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)-3-(2-(3-(benzyloxy)phenyl)acetyl)urea(150 mg, 0.31 mmol) in a mixture of 5 mL of EtOAc and 3 mL of MeOH wasadded 10% Pd/C (200 mg). The suspension was stirred under H₂ atmospherefor 1 h. Filtration, followed by concentration, provided the titlecompound (77 mg, 63%). ¹H NMR (DMSO-d₆) δ 10.95 (s, 1H), 10.54 (s, 1H),9.35 (s, 1H), 7.74 (d, 1H, J=6.0 Hz), 7.68 (dd, 1H, J=13.0, 2.0 Hz),7.30 (dd, 1H, J=9.0, 1.1 Hz), 7.23 (t, 1H, J=9.0 Hz), 7.07 (t, 1H, J=8.0Hz), 6.69 (s, 1H), 6.68 (d, 1H, J=7.0 Hz), 6.62 (dd, 1H, J=7.0, 2.0 Hz),6.10 (dd, 1H, J=6.0, 2.0 Hz), 5.90 (s, 2H), 5.73 (d, 1H, J=2.0 Hz), 3.27(s, 2H); MS (ESI⁺) m/z 397 (M+H)⁺.

Example 144

3-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-1-(2-(4-fluorophenyl)acetyl)-1-methylurea,hydrochloride salt

A) 2-(4-Fluorophenyl)-N-methylacetamide

To a solution of methylamine in THF (2.0 M, 5 mL, 10 mmol) was added4-fluorophenylacetyl chloride (518 mg, 3.0 mmol) at −78° C. The reactionmixture was stirred from −78° C. to room temperature for 1 h. Thesolution was diluted with H₂O and extracted with EtOAc. The organiclayer was washed with brine and dried over MgSO₄. Filtration, followedby concentration, provided the title compound (490 mg, 98%). MS (ESI⁺)m/z 168 (M+H)⁺.

B)3-(4-(2-Carbamoylpyridin-4-yloxy)-3-fluorophenyl)-1-(2-(4-fluorophenyl)acetyl)-1-methylurea

To a solution of 2-(4-fluorophenyl)-N-methylacetamide (89 mg, 0.53 mmol)in 2 mL of THF at −78° C. was added MeLi in Et₂O (1.6 M, 0.34 mL, 0.55mmol). The solution was stirred at −78° C. for 5 min and then 20%phosgene in toluene (1.9 M, 0.29 mL, 0.55 mmol) was introduced quickly.After 2 min, 4-(4-amino-2-fluorophenoxy)picolinamide (Compound B′ ofExample 24, 100 mg, 0.40 mmol) was added, followed by the addition ofDMF (2 mL) and DIEA (0.4 mL). The reaction mixture was stirred at roomtemperature for 1 h and quenched with H₂O. The solution was thenextracted with EtOAc and the organic layer was washed with brine, driedover MgSO₄. After filtration and concentration, the residue was purifiedby silica gel chromatography to give the title compound (77 mg, 33%). MS(ESI⁺) m/z 441 (M+H)⁺.

C)3-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-1-(2-(4-fluorophenyl)acetyl)-1-methylurea,hydrochloride salt

The title compound was prepared in a similar manner described in Step D′of Example 24. Yield: 24%. ¹H NMR (DMSO-d₆) δ 13.20 (s, 1H), 11.17 (s,1H), 7.90 (d, 1H, J=7.0 Hz), 7.78-7.74 (m, 3H), 7.39-7.34 (m, 2H),7.23-7.21 (m, 2H), 7.10-7.05 (m, 2H), 6.63 (dd, 1H, J=7.0, 2.0 Hz), 6.08(d, 1H, J=2.0 Hz), 4.00 (s, 2H), 3.24 (s, 3H); MS (ESI⁺) m/z 413 (M+H)⁺.

Example 145

(R)—N¹-(2-Amino-2-oxo-1-phenylethyl)-N³-(4-(2-aminopyridin-4-yloxy)-2,5-difluorophenyl)malonamide,trifluoroacetic acid salt

A) Ethyl3-(4-(2-aminopyridin-4-yloxy)-2,5-difluorophenylamino)-3-oxopropanoate

Ethyl3-(4-(2-carbamoylpyridin-4-yloxy)-2,5-difluorophenylamino)-3-oxopropanoate(Compound A of Example 116, 0.73 g, 1.9 mmol) was converted to the titlecompound (0.24 g, 35%) in a manner similar to the preparation ofCompound E of Example 112. MS (ESI⁺) m/z 352 (M+H)⁺.

B) 3-(4-(2-Aminopyridin-4-yloxy)-2,5-difluorophenylamino)-3-oxopropanoicacid

Ethyl3-(4-(2-aminopyridin-4-yloxy)-2,5-difluorophenylamino)-3-oxopropanoate(0.24 g, 0.68 mmol) was converted to the title compound (0.039 mg, 18%)in a manner similar to the preparation of Compound B of Example 116.HRMS (ESI⁺), Calcd.: 324.0796 (M+H)⁺. found: 324.0795 (M+H)⁺.

C)(R)—N′-(2-Amino-2-oxo-1-phenylethyl)-N³-(4-(2-aminopyridin-4-yloxy)-2,5-difluorophenyl)malonamidetrifluoroacetic acid salt

3-(4-(2-Aminopyridin-4-yloxy)-2,5-difluorophenylamino)-3-oxopropanoicacid (0.039 g, 0.12 mmol) was coupled with (R)-2-amino-2-phenylacetamidehydrochloride (Bachem, 0.023 g, 0.12 mmol), in a manner similar to thepreparation of Example 103, to afford the title compound (0.0048 g, 7%).¹H NMR (DMSO-d₆) δ 10.33 (s, 1H), 8.77 (d, 1H, J=7.8 Hz), 8.10-8.19 (m,1H), 7.90 (d, 1H, J=7.2 Hz), 7.60-7.75 (m, 4H), 7.17-7.39 (m, 6H),6.66-6.69 (m, 1H), 6.11 (s, 1H), 5.35 (d, 1H, J=7.8 Hz); HRMS (ESI⁺),Calcd.: 456.1483 (M+H)⁺. found: 456.1487 (M+H)⁺.

Example 146

N-(4-(2-Aminopyridin-4-yloxy)phenyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide,hydrochloride salt

A)4-(4-(2-Oxo-1-phenyl-1,2-dihydropyridine-3-carboxamido)phenoxy)picolinamide

4-(4-Aminophenoxy)picolinamide (Compound A of Example 142, 0.030 g, 0.13mmol) was coupled with Compound C of Example 57 (0.028 g, 0.13 mmol), ina manner similar to the preparation of Compound A of Example 115, toafford the title compound (0.057 g, 100%) which was used without furtherpurification. MS (ESI⁺) m/z 427 (M+H)⁺.

B)N-(4-(2-Aminopyridin-4-yloxy)phenyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide,hydrochloride salt

4-(4-(2-Oxo-1-phenyl-1,2-dihydropyridine-3-carboxamido)phenoxy)picolinamide(0.055, 0.13 mmol) was converted to the title compound (0.0093 g, 16%)in a manner similar to the preparation of Compound E of Example 112. ¹HNMR (CD₃OD) δ 12.10 (s, 1H), 8.59-8.61 (m, 1H), 7.88-7.90 (m, 1H),7.69-7.76 (m, 3H), 7.39-7.53 (m, 5H), 7.10-7.13 (m, 2H), 6.66 (t, 1H,J=6.9 Hz), 6.53-6.55 (m, 1H), 6.07-6.08 (m, 1H), 4.75 (br s, 2H); HRMS(ESI⁺), Calcd.: 399.1457 (M+H)⁺. found: 399.1453 (M+H)⁺.

Example 147

N-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-1-benzyl-2-oxo-1,2-dihydropyridine-3-carboxamide,hydrochloride salt

A) Methyl 1-benzyl-2-oxo-1,2-dihydropyridine-3-carboxylate

A heterogeneous mixture of methyl 2-oxo-2H-pyran-3-carboxylate (Aldrich,2.0 g, 13 mmol, 1.0 eq) and 4-fluorobenzylamine (1.5 mL, 13 mmol, 1.0eq) in DMF (10 ml) were stirred at room temperature for 3 h. Thereaction mixture was treated with EDCI (3.4 g, 18 mmol, 1.4 eq) and DMAP(0.11 g, 9.91 mmol, 0.07 eq) at room temperature and the resultingsolution was stirred for 12 h. The reaction mixture was quenched with 1Naqueous HCl and the solution was extracted with ethyl acetate (4×50 mL).The combined organic extracts were washed with 10% aqueous LiCl (3×70mL), dried (Na₂SO₄), filtered and the filtrate concentrated in vacuo toafford the product (2.5 g, 73%) as a solid, that was used withoutfurther purification. ¹H NMR (DMSO-d₆) δ 8.17-8.20 (m, 1H), 8.03-8.05(m, 1H), 7.38-7.46 (m, 2H), 7.16-7.22 (m, 2H), 6.37 (dd, 1H, J=6.94 Hz),5.13 (s, 2H), 3.73 (s, 3H); HRMS (ESI⁺), Calcd.: 262.0879. found:262.0885.

B) 1-Benzyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid

A solution of methyl 1-benzyl-2-oxo-1,2-dihydropyridine-3-carboxylate(2.4 g, 9.2 mmol, 1.0 eq) in MeOH (25 mL) was treated with 5N aqueoussodium hydroxide (4.6 mL, 24 mmol, 2.6 eq) at room temperature and thereaction mixture was stirred for 15 h. The reaction mixture was thenconcentrated in vacuo, diluted with water and the solution was extractedwith ethyl acetate, discarding the organic fraction. The aqueousfraction was cooled to 0° C. and was acidified with concentrated HCl.The resulting solid was filtered, washed with water and the solid driedin vacuo to afford the product (1.6 g, 70%), which was used withoutfurther purification. ¹H NMR (DMSO-d₆)

δ 8.39-8.44 (m, 2H), 7.42-7.46 (m, 2H), 7.18-7.24 (m, 2H), 6.78 (dd, 1H,J=6.98 Hz), 5.31 (s, 2H); HRMS (ESI⁺), Calcd.: 248.0723. found:248.0718.

C)4-(4-(1-Benzyl-2-oxo-1,2-dihydropyridine-3-carboxamido)-2-fluorophenoxy)picolinamide

A homogeneous solution of1-benzyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (0.10 g, 0.41 mmol,1.0 eq), 4-(4-amino-2-fluorophenoxy)picolinamide (0.10 g, 0.41 mmol, 1.0eq) and TBTU (0.17 g, 0.45 mmol, 1.1 eq) in DMF (2 mL) was treated withDIPEA (0.18 mL, 1.0 mmol, 2.5 eq) at room temperature and the reactionmixture was stirred for 12 h. The reaction mixture was quenched with 10%aqueous LiCl (15 mL) and the resulting solution was extracted with ethylacetate (4×40 mL). The combined organic extracts were washed with 10%aqueous LiCl (4×50 mL), dried (Na₂SO₄), filtered and the filtrateconcentrated in vacuo. The residue was purified by flash columnchromatography (SiO₂, eluting with ethyl acetate) to afford the product(0.13 g, 67%) as a solid. ¹H NMR (DMSO-d₆) δ 12.26 (s, 1H), 8.49-8.56(m, 2H), 8.33-8.36 (m, 1H), 8.15 (br m, 1H), 8.03-8.07 (m, 1H),7.74-7.75 (m, 1H), 7.51-7.54 (m, 1H), 7.41-7.46 (m, 4H), 7.20-7.24 (m,3H), 6.71 (dd, 1H, J=6.89 Hz), 5.32 (s, 2H) HRMS (ESI⁺), Calcd.:477.1374. found: 477.1378.

D)N-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)-1-benzyl-2-oxo-1,2-dihydropyridine-3-carboxamide,hydrochloride salt

Bis(trifluoroacetoxy)iodobenzene (0.12 g, 0.28 mmol, 1.1 eq) was addedto a solution of4-(4-(1-benzyl-2-oxo-1,2-dihydropyridine-3-carboxamido)-2-fluorophenoxy)picolinamide(0.12 g, 0.26 mmol, 1.0 eq), and water (0.01 mL, 0.51 mmol, 20 eq) inDMF (1 mL) at room temperature. Pyridine (0.065 mL, 0.77 mmol, 3.0 eq)was added to the homogeneous mixture and the reaction mixture wasstirred at room temperature for 12 h. The reaction mixture was quenchedwith 1N aqueous HCl (1 mL) and the resulting solution was extracted withdiethyl ether (3×5 mL), discarding the organic layer. The aqueousfraction was neutralized with 1N aqueous NaOH and the resulting solutionwas extracted with 9/1 CHCl₃/MeOH (4×10 mL). The combined organicextracts were dried (Na₂SO₄), filtered and the filtrate was concentratedin vacuo. The residue was purified by flash chromatography (SiO₂,eluting 0-3% MeOH in CHCl₃) and the appropriate fractions wereconcentrated in vacuo. The free base was dissolved in THF, cooled to 0°C. and the homogeneous solution treated with anhydrous 4N HCl indioxane. The reaction mixture was warmed to room temperature,concentrated in vacuo and the residue triturated with diethyl ether,discarding the filtrate. The solid was dried in vacuo to afford thetitle compound (0.082 g, 66%) as a HCl salt. ¹H NMR (DMSO-d₆) δ 13.66(br s, 1H), 8.49-8.51 (m, 1H), 8.39-8.49 (m, 1H), 8.37-8.39 (m, 1H),8.00-8.09 (m, 3H), 7.54-7.56 (m, 1H), 7.43-7.48 (m, 3H), 7.19-7.24 (m,2H), 6.69-6.72 (m, 2H), 6.21-6.22 (m, 1H), 5.32 (s, 2H); HRMS (ESI⁺),Calcd.: 449.1425. found: 449.1406.

Example 148

N-(4-Fluorobenzyl)-N-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)cyclopropane-1,1-dicarboxamide

A) 1-((4-Fluorobenzyl)carbamoyl)cyclopropanecarboxylic acid

To a solution of 1,1-cyclopropanecarboxylic acid (Aldrich, 390 mg, 3.0mmol) in THF (5 mL) at 0° C. was added triethylamine (0.42 mL, 3.0mmol). After stirring for 30 min at 0° C., thionyl chloride (0.219 mL,3.0 mmol) was added to the reaction mixture. The mixture was stirred at0° C. for an additional 30 min and a solution of 4-fluorobenzylamine(Aldrich, 375 mg, 3.0 mmol) in THF (2 mL) was added. The reactionmixture was stirred at 0° C. for 2 h, diluted with ethyl acetate (100mL) and extracted with 1 N NaOH (10 mL). The aqueous phase was acidifiedwith 1 N HCl to pH 1-2. The solid which formed was collected byfiltration (343 mg, 48%). MS (ESI⁺) m/z 238.24 (M+H)⁺.

B)N-(4-Fluorobenzyl)-N-(4-(2-carbamoylpyridin-4-yloxy)-3-fluorophenyl)cyclopropane-1,1-dicarboxamide

To a solution of 4-(4-amino-2-fluorophenoxy)picolinamide (Compound B′ ofExample 24, 49 mg, 0.2 mmol) in DMF (2 mL) at room temperature was added1-((4-fluorobenzyl)carbamoyl)cyclopropanecarboxylic acid (47 mg, 0.2mmol), HATU (Perseptive Biosystem, 114 mg, 0.3 mmol), and DIEA (0.2 mL,1.1 mmol). The reaction mixture was stirred at rt for 2 h, and thenquenched by adding 4 mL of methanol. The reaction mixture was purifiedby prep. HPLC. The desired fractions were combined, neutralized with aq.K₂HPO₄, and concentrated in vacuo. The solid which formed was collectedby filtration (29 mg, 31%). ¹H NMR (DMSO-d₆) δ 10.78 (br s, 1H), 8.53(d, 1H, J=5.5 Hz), 8.47 (t, 1H, J=5.5 Hz), 8.11 (s, 1H), 7.88 (dd, 1H,J=13.2, 2.3 Hz), 7.70 (s, 1H), 7.47 (d, 1H, J=9.2 Hz), 7.38 (t, 1H,J=9.2 Hz), 7.34-7.29 (m, 3H), 7.22 (dd, 1H, J=5.5, 2.8 Hz), 7.13 (t, 2H,J=8.8 Hz), 4.30 (d, 2H, J=5.5 Hz), 1.37 (d, 4H, J=10.6 Hz); MS (ESI⁺)m/z 467.12 (M+H)⁺.

C)N-(4-Fluorobenzyl)-N-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)cyclopropane-1,1-dicarboxamide

To a solution ofN-(4-fluorobenzyl)-N-(4-(2-carbamoylpyridin-4-yloxy)-3-fluorophenyl)cyclopropane-1,1-dicarboxamide(25 mg, 0.05 mmol) in DMF (1 mL) at room temperature was added pyridine(0.2 mL), water (0.1 mL), and [bis(trifluoroacetoxyl)-iodo]benzene(Aldrich, 34 mg, 0.08 mmol). The reaction mixture was stirred at rt for2 h, and then quenched by adding 2 mL of methanol. The reaction mixturewas purified by prep. HPLC. The desired fractions were combined,neutralized with aq. K₂HPO₄, concentrated and extracted with ethylacetate. The organic extracts were dried over MgSO₄ and concentrated invacuo. The residue was dissolved in a small amount of CH₃CN/H₂O andlyophillized to dryness to give the title compound (21 mg, 90%) as awhite solid. ¹H NMR (DMSO-d₆) δ 10.87 (br s, 1H), 8.44 (t, 1H, J=6.0Hz), 7.91 (d, 1H, J=6.6 Hz), 7.88 (d, 1H, J=13.2 Hz), 7.37-7.29 (m, 6H),7.13 (t, 2H, J=8.8 Hz), 4.29 (d, 2H, J=6.1 Hz), 1.38 (d, 4H, J=2.2 Hz);MS (ESI⁺) m/z 439.14 (M+H)⁺.

1. A compound having Formula I:

or an enantiomer, diastereomer, or pharmaceutically acceptable saltthereof wherein: R¹ is alkyl, substituted alkyl, cycloalkyl, substitutedcycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclo, or substituted heterocyclo; each R² is independently H,halogen, cyano, NO₂, OR⁵, NR⁶R⁷, alkyl, and/or haloalkyl; B is O, NR⁸,NR⁸CH₂, S, SO, SO₂, or CR⁹R¹⁰; V is NR¹¹ or —(CR³⁷R³⁸)_(p)— providedthat when V is NR¹¹, R¹ is alkyl, substituted alkyl, cycloalkyl, orsubstituted cycloalkyl; W and X are independently CH and/or N; Y is O,S, or NR¹²; Z is —CR¹³R¹⁴— or —(CR¹³R¹⁴)_(l)NR¹⁵—; l is 0 to 2; n is 0to 4 if W and X are both CH, 0 to 3 if only one of X and W is N, and 0to 2 if X and W are both N; p is 1 to 4; R³, R⁵, R⁶, R⁷, R⁸, R¹¹, R¹²,and R¹⁵ are independently H and/or alkyl; R⁹ and R¹⁰ are independentlyH, halogen, alkyl, and/or hydroxyalkyl; R¹³ and R¹⁴ are independently H,halogen, alkyl, haloalkyl, and/or hydroxyalkyl, or taken together withthe carbon atom to which they are attached to form a carbocyclic orheterocyclic ring of 3 to 8 atoms; A is:

R¹⁶, R¹⁷, R¹⁸, and R¹⁹ are independently H, halogen, NR³⁰R³¹, OR³²,CO₂R³³, CONR³⁴R³⁵, SO₂R³⁶, alkyl, haloalkyl, hydroxyalkyl, substitutedalkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, —CN, aryl, substituted aryl, heteroaryl,and/or substituted heteroaryl; R³⁰, R³¹, R³², R³³, R³⁴, R³⁵, and R³⁶ areindependently H, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,alkoxycarbonyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclo, and/or substituted heterocyclo; and R³⁷ and R³⁸are each independently H, halogen, and/or alkyl; wherein: saidsubstituted alkyl, said substituted cycloalkyl, said substitutedalkenyl, and said substituted alkynyl are substituted with one or moresubstituents independently selected from phenyl, halophenyl, amino,amido, —CN, —C(═O)OH, —C(═O)OCH₃, halogen, hydroxy, and alkoxy; and saidsubstituted aryl, said substituted heteroaryl, and said heterocyclo aresubstituted with one or more substituents independently selected fromalkyl, haloalkyl, hydroxyalkyl, alkoxy, —CN, halogen, phenyl,halophenyl, hydroxy, and amino.
 2. The compound according to claim 1 oran enantiomer, diastereomer, or pharmaceutically acceptable saltthereof, wherein: W and X are each CH.
 3. The compound according toclaim 2 or an enantiomer, diastereomer, or pharmaceutically acceptablesalt thereof, wherein B is O.
 4. The compound according to claim 2 or anenantiomer, diastereomer, or pharmaceutically acceptable salt thereof,wherein: Z is NR¹⁵; and V is CR³⁷R³⁸—.
 5. The compound according toclaim 4 or an enantiomer, diastereomer, or pharmaceutically acceptablesalt thereof, wherein: Y is O or S; R¹ is alkyl optionally substitutedwith one or more substituents selected from phenyl, fluorophenyl, amino,amido, —CN, —C(═O)OH, and/or —C(═O)OCH₃, or phenyl optionallysubstituted with halo; each R² is independently F, Cl, —CH₃, and/or—CF₃; R³ is H; R¹⁵ is H or —CH₃; and R³⁷ and R³⁸ are independently Hand/or —CH₃.
 6. The compound according to claim 5 or an enantiomer,diastereomer, or pharmaceutically acceptable salt thereof, wherein B isO.
 7. The compound according to claim 6 or an enantiomer, diastereomer,or pharmaceutically acceptable salt thereof, wherein R¹⁸ and R¹⁹ areeach H.
 8. The compound according to claim 2 or an enantiomer,diastereomer, or pharmaceutically acceptable salt thereof, wherein: Z is—CR¹³R¹⁴—; and V is —NR¹¹—.
 9. The compound according to claim 8 or anenantiomer, diastereomer, or pharmaceutically acceptable salt thereof,wherein: Y is O or S; R¹ is alkyl or cycloalkyl optionally substitutedwith one or more substituents independently selected from phenyl,fluorophenyl, amino, amido, —CN, —C(═O)OH, and/or —C(═O)OCH₃; R¹¹ is Hor —CH₃; each R² is independently F, Cl, —CH₃, and/or —CF₃; R³ is H; andR¹³ and R¹⁴ are independently H and/or —CH₃, or taken together with thecarbon atom to which they are attached to form a carbocyclic ring of 3to 5 atoms.
 10. The compound according to claim 9 or an enantiomer,diastereomer, or pharmaceutically acceptable salt thereof, wherein B isO.
 11. The compound according to claim 10 or an enantiomer,diastereomer, or pharmaceutically acceptable salt thereof, wherein R¹⁸and R¹⁹ are each H.
 12. The compound according to claim 1 or anenantiomer, diastereomer, or pharmaceutically acceptable salt thereof,wherein: B is O, NHCH₂, CH₂, or CH(OH); Y is O or S; and Z is —CH₂— or—NH—.
 13. The compound according to claim 1 or an enantiomer,diastereomer, or pharmaceutically acceptable salt thereof, having anIC₅₀ value of less than about 1.0 μM.
 14. A pharmaceutical compositioncomprising a therapeutically effective amount of a compound according toclaim 1 or an enantiomer, diastereomer, or pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier.
 15. A compoundor an enantiomer, diastereomer, or pharmaceutically acceptable saltthereof, selected from:1-(2-(4-fluorophenyl)acetyl)-3-(4-(pyridin-4-yloxy)phenyl)thiourea (3):1-(4-(2-chloropyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)thiourea(21);1-(3-fluoro-4-(pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea(23);1-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea(24);1-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)thiourea(27);1-(3-fluoro-4-(2-(4-fluorophenylamino)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea(28);1-(4-(3-ethylpyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,hydrochloride salt (33);1-(4-(2-amino-3-ethylpyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,trifluoroacetic acid salt (34);1-(4-(3-(2-(4-aminocyclohex-1-enyl)ethynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea(35);1-(4-(3-(3-(3-(aminomethyl)azetidin-1-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,trihydrochloride salt (36);1-(4-(3-(3-(3-aminoazetidin-1-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,trihydrochloride salt (37);1-(3-fluoro-4-(3-(3-(piperazin-1-yl)prop-1-ynyl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea,trihydrochloride salt (38);1-(4-(3-(3-(4-aminopiperidin-1-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,trihydrochloride salt (39);(±)-1-(4-(3-(3-(3-aminopyrrolidin-1-yl)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,trihydrochloride salt (40);1-(3-fluoro-4-(3-(3-((3R,4R)-3-hydroxy-4-(pyrrolidin-1-yl)pyrrolidin-1-yl)prop-1-ynyl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea,trihydrochloride salt (41);1-(3-fluoro-4-(3-(3-(2-(pyrrolidin-1-yl)acetamido)prop-1-ynyl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea,dihydrochloride salt (42);1-(3-fluoro-4-(3-(3-(2-(4-hydroxypiperidin-1-yl)acetamido)prop-1-ynyl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea,dihydrochloride salt (43);(S)-1-(3-fluoro-4-(3-(3-(2-(pyrrolidin-1-ylmethyl)pyrrolidine-1-carboxamido)prop-1-ynyl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea,dihydrochloride salt (44);(E)-1-(4-(3-(3-(4-aminopiperidin-1-yl)-3-oxoprop-1-enyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,ditrifluoroacetic acid salt (45);1-(3-fluoro-4-(3-(2-(pyridin-2-yl)ethynyl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea,dihydrochloride salt (46);1-(3-fluoro-4-(3-(2-(pyridin-3-yl)ethynyl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea,dihydrochloride salt (47);1-(4-(3-(4-(2-amino-2-oxoethyl)phenyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,hydrochloride salt (59);1-(4-(3-(4-(aminomethyl)phenyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,trifluoroacetic acid salt (60);1-(3-fluoro-4-(3-(6-(piperazin-1-yl)pyridin-3-yl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea,hydrochloride salt (61);N¹—((R)-2-amino-2-oxo-1-phenylethyl)-N³-(3-fluoro-4-(3-(6-(piperazin-1-yl)pyridin-3-yl)pyridin-4-yloxy)phenyl)malonamide,hydrochloride salt (63);1-(3-fluoro-4-(3-(pyridin-3-yl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea,hydrochloride salt (64);1-(3-fluoro-4-(3-(4-(piperazin-1-yl)phenyl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea,trihydrochloride salt (65);1-(4-(3-aminopyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea(72);1-(4-(3-((1S,4S)-4-aminocyclohexanecarboxamido)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,trifluoroacetic acid salt (73);1-(4-(3-((1R,4R)-4-aminocyclohexanecarboxamido)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,bis-trifluoroacetic acid salt (74);1-(4-(3-((1R,4R)-4-(aminomethyl)cyclohexanecarboxamido)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea(75);1-(4-(3-(cyclohexanecarboxamido)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea(76);1-(4-(3-(4-aminopiperidine-1-carboxamido)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,bis-trifluoroacetic acid salt (77);1-(4-(2-amino-3-(4-(2-amino-2-oxoethyl)phenyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,trifluoroacetic acid salt (78);1-(4-(2-Amino-3-(2-(pyridin-2-yl)ethynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,dihydrochloride salt (79);1-(4-(2-acetamidopyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,hydrochloride salt (80);1-(3-fluoro-4-(2-(2-morpholinoethylamino)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea,dihydrochloride salt (82);1-(3-fluoro-4-(2-(3-morpholinopropylamino)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea,hydrochloride salt (83);1-(4-(2-(3-(dimethylamino)propylamino)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,hydrochloride salt (84);1-(4-(2-(4-(dimethylamino)butylamino)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,hydrochloride salt (85);1-(4-(2,6-diaminopyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,hydrochloride salt (86);1-(4-((2-(3-(dimethylamino)propylamino)pyridin-4-yl)methyl)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,dihydrochloride salt (87);1-(4-((2-(3-(dimethylamino)propylamino)pyridin-4-yl)(hydroxy)methyl)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea(88);1-(4-((2-aminopyridin-4-yl)methyl)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,trifluoroacetic acid salt (89);1-(4-(2-carbamoylpyridin-4-yloxy)-3-chlorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea(90);1-(4-(2-aminopyridin-4-yloxy)-3-chlorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,hydrochloride salt (91);1-(4-(2-aminopyridin-4-yloxy)-2-chlorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea(92);1-(4-(2-carbamoylpyridin-4-yloxy)-3-methylphenyl)-3-(2-(4-fluorophenyl)acetyl)urea(93);1-(4-(2-aminopyridin-4-yloxy)-3-methylphenyl)-3-(2-(4-fluorophenyl)acetyl)urea,hydrochloride salt (94);1-(4-(2-aminopyridin-4-yloxy)-2-(trifluoromethyl)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea,hydrochloride salt (95);1-(4-(2-aminopyridin-4-yloxy)-2-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,trifluoroacetic acid salt (96);1-(4-(2-aminopyridin-4-yloxy)-2,3-difluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,trifluoroacetic acid salt (97);(S)—N¹-(2-amino-2-oxo-1-phenylethyl)-N³-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)malonamide,hydrochloride salt (102);(R)—N¹-(2-amino-2-oxo-1-phenylethyl)-N³-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)malonamide,hydrochloride salt (103); (S)-methyl2-(3-(4-(2-aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanamido)-2-phenylacetate,hydrochloride salt (104); (R)-methyl2-(3-(4-(2-aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanamido)-2-phenylacetate,hydrochloride salt (105);N¹-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)-N³-cyclopentylmalonamide,hydrochloride salt (106);N¹-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)-N³-cyclohexylmalonamide,hydrochloride salt (107);N¹-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)-N³-neopentylmalonamide,hydrochloride salt (108);(S)-2-(3-(4-(2-aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanamido)-2-phenylaceticacid, hydrochloride salt (109);1-(4-(2-aminopyridin-4-yloxy)-2,5-difluorophenyl)-3-(2-(4-fluorophenyl)-acetyl)urea,hydrochloric acid salt (112);1-(4-(2-aminopyridin-4-yloxy)-3,5-difluorophenyl)-3-(2-(4-fluorophenyl)-acetyl)urea,trifluoroacetic acid salt (113);(O)—N¹-(4-(2-aminopyridin-4-yloxy)-2,5-difluorophenyl)-N³-(1-phenylethyl)malonamide,hydrochloric acid salt (116);(±)—N¹-(4-(2-aminopyridin-4-yloxy)-2,5-difluorophenyl)-N³-(cyano(phenyl)-methyl)malonamide,trifluoroacetic acid salt (117);(±)—N¹-(2-amino-1-phenylethyl)-N³-(4-(2-aminopyridin-4-yloxy)-2,5-difluorophenyl)malonamide,bistrifluoroacetic acid salt (118);1-(4-(2-amino-3-(hydroxymethyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,hydrochloride salt (126);1-(4-(2-amino-3-((methylamino)methyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,hydrochloride salt (127);1-(4-(2-amino-3-((2-hydroxyethylamino)methyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,trifluoroacetic acid salt (128);1-(4-(2-amino-3-(2-(pyridin-2-yl)ethynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,dihydrochloride salt (131);1-(4-(2-amino-3-(2-(5-aminopyridin-2-yl)ethynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,dihydrochloride salt (133);1-(4-(2-amino-3-(3-((3R,4R)-3-hydroxy-4-(pyrrolidin-1-yl)pyrrolidin-1-yl)-3-methylbut-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,trihydrochloride salt (135);1-(3-fluoro-4-(3-(3-hydroxyprop-1-ynyl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea,hydrochloride salt (136);1-(4-(2-amino-3-(3-aminoprop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,dihydrochloride salt (138);1-(4-(2-amino-3-(3-hydroxyprop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,hydrochloride salt (139);1-(4-(2-amino-3-(3-(dimethylamino)prop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea,dihydrochloride salt (141);1-(4-(2-aminopyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea,hydrochloride salt (142);1-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)-3-(2-(3-hydroxyphenyl)acetyl)urea(143);3-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)-1-(2-(4-fluorophenyl)acetyl)-1-methylurea,hydrochloride salt (144);(R)—N¹-(2-amino-2-oxo-1-phenylethyl)-N³-(4-(2-aminopyridin-4-yloxy)-2,5-difluorophenyl)malonamide,trifluoroacetic acid salt (145); andN-(4-fluorobenzyl)-N-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)cyclopropane-1,1-dicarboxamide(148).